Crystalline forms of 3-(imidazo[1,2-b] pyridazin-3-ylethynyl)-4-methyl-n-benzamide and its mono hydrochloride salt

ABSTRACT

Novel crystalline forms of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide free base and 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide mono hydrochloride, pharmaceutical compositions thereof and methods of their preparation and use are disclosed herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 61/736,543, filed Dec. 12, 2012; U.S. Provisional PatentApplication Ser. No. 61/737,007, filed Dec. 13, 2012; and U.S.Provisional Patent Application Ser. No. 61/788,208, filed Mar. 15, 2013,which are incorporated herein by reference in their entireties.

BACKGROUND

The instant application is directed to novel crystalline forms of3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamideand3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemono hydrochloride, compositions comprising such crystalline forms, andto methods of their preparation and use.

3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidehas the chemical formula C₂₉H₂₇F₃N₆O which corresponds to a formulaweight of 532.56 g/mol. Its chemical structure is shown below:

The CAS Registry number for3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamideis 943319-70-8.

3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemono hydrochloride has the chemical formula C₂₉H₂₈ClF₃N₆O whichcorresponds to a formula weight of 569.02 g/mol. Its chemical structureis shown below:

The CAS Registry number for3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemono hydrochloride is 1114544-31-8.

The United States Adopted Name (USAN) and International NonproprietaryName (INN) of3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamideis ponatinib. Alternative chemical names for ponatinib includebenzamide,3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]and3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide.

The United States Adopted Name (USAN) and International NonproprietaryName (INN) of3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemono hydrochloride is ponatinib hydrochloride. Alternative chemicalnames for ponatinib hydrochloride include benzamide,3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-,hydrochloride (1:1) and3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemonohydrochloride.

Ponatinib is a multi-targeted tyrosine-kinase inhibitor useful for thetreatment of chronic myeloid leukemia (CML) and other diseases.Ponatinib hydrochloride is a small molecule pan-BCR-ABL inhibitor inclinical development for the treatment of adult patients with chronicphase, accelerated phase, or blast phase CML or Philadelphia chromosomepositive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerantto prior tyrosine-kinase inhibitor therapy. Other tyrosine-kinaseinhibitors relevant to such CML or Ph+ ALL therapy include GLEEVEC®(imatinib mesylate) and TASIGNA® (nilotinib) (both from Novartis AG),SPRYCEL® (dasatinib) (from Bristol Myers Squibb Company) and BOSULIF®(bosutinib) (from Pfizer Inc). A New Drug Application (NDA) forponatinib hydrochloride was filed with the United States FDA on Jul. 30,2012. The US FDA approved the NDA on Dec. 14, 2012, and ponatinibhydrochloride is marketed under the brand name ICLUSIG® (ponatinib).

In addition, ponatinib hydrochloride is potentially clinically usefulfor the treatment of other disorders or conditions implicated by theinhibition of other protein kinases. Such kinases and their associateddisorders or conditions are mentioned in O'Hare, T., et al., CancerCell, Volume 16, Issue 5, 401-412 (2009) and WO 2011/053938, both ofwhich are hereby incorporated herein by reference for all purposes.

Having an understanding of the potential polymorphic forms for activepharmaceutical ingredients (API) such as ponatinib and ponatinibhydrochloride is useful in the development of drugs. This is because notknowing the specific polymorphic form present or desired in the API mayresult in inconsistent manufacturing of the API and as a result, resultswith the drug may vary between various lots of the API. In addition, itis important to discover the potential polymorphic forms of an API sothat one can systematically determine the stability of that form over aprolonged period of time for similar reasons. Once a specificpolymorphic form is selected for pharmaceutical development, it isimportant to be able to reproducibly prepare that polymorphic form. Itis also desirable for there to be a process for making APIs such asponatinib and ponatinib hydrochloride in high purity due to thepotential for impurities to affect the performance of the drug.

The earliest patent publication known by Applicant to disclose thechemical structure of ponatinib hydrochloride is WO 2007/075869, whichis also owned by Applicant (ARIAD Pharmaceuticals, Inc.) and is herebyincorporated herein by reference for all purposes. Example 16 of WO2007/075869 states that the product was obtained as a solid: 533 m/z(M+H). This mass corresponds to the free base of ponatinib. Example 16also discusses the preparation of a mono hydrochloride salt ofponatinib. Example 16 neither specifically mentions that the ponatinibhydrochloride obtained was crystalline, nor specifies any particularcrystalline forms of ponatinib hydrochloride.

U.S. Ser. No. 11/644,849, which published as US 2007/0191376, is acounterpart application to WO 2007/075869 and granted on Feb. 14, 2012as U.S. Pat. No. 8,114,874, which is hereby incorporated herein byreference for all purposes. U.S. Ser. No. 13/357,745 is a continuingapplication of U.S. Ser. No. 11/644,849, which also is herebyincorporated herein by reference for all purposes.

Additional patent applications owned by Applicant that cover ponatinibhydrochloride and published as of the filing date of this applicationinclude WO 2011/053938 and WO 2012/139027, both of which are herebyincorporated herein by reference for all purposes. Like WO 2007/075869,neither of WO 2011/053938 or WO 2012/139027 specifies any particularcrystalline forms of ponatinib hydrochloride.

SUMMARY

It has now been discovered that both ponatinib and ponatinibhydrochloride can exist in certain crystalline and other polymorphicforms, certain of which are suitable for pharmaceutical formulationdevelopment.

In one aspect, the present disclosure is directed to polymorphs ofponatinib. The polymorphs of ponatinib are herein designated as Form A,Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J,and Form K.

In another aspect, the present disclosure is directed to pharmaceuticalcompositions comprising a therapeutically effective amount of apolymorph of ponatinib disclosed herein and at least onepharmaceutically acceptable carrier, vehicle or excipient.

In another aspect, the present disclosure is directed to substantiallypure crystalline forms of ponatinib hydrochloride. The substantiallypure crystalline forms of ponatinib hydrochloride are herein designatedas Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, FormI, Form J, and Form K.

In another aspect, the present disclosure is directed to pharmaceuticalcompositions comprising a therapeutically effective amount of asubstantially pure crystalline form of ponatinib hydrochloride disclosedherein and at least one pharmaceutically acceptable carrier, vehicle orexcipient.

In another aspect, the present disclosure provides a process forpreparing a substantially pure crystalline form of ponatinibhydrochloride by contacting ponatinib with hydrochloric acid.

In another aspect, the present disclosure is directed to a method oftreating a disorder or condition in a human that responds to theinhibition of a protein kinase by administering to the human atherapeutically effective amount of a polymorph of ponatinib disclosedherein. In certain embodiments, the disorder or condition is chronicmyeloid leukemia (CML).

In another aspect, the present disclosure is directed to a method oftreating a disorder or condition in a human that responds to theinhibition of a protein kinase by administering to the human atherapeutically effective amount of a substantially pure crystallineform of ponatinib hydrochloride disclosed herein. In certainembodiments, the disorder or condition is chronic myeloid leukemia (CML)or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) when the protein kinase is Bcr-Abl or a mutant form thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinventions. The inventions may be better understood by reference to oneor more of these drawings in combination with the detailed descriptionof specific embodiments presented herein.

FIG. 1 is a summary of the eleven solid forms of ponatinib hydrochloridethat include HCl polymorphs and pseudo-polymorphs that are identified asForms A through K and that were discovered and are disclosed herein.

FIG. 2 is a summary of certain of the solid forms of ponatinibhydrochloride identified in FIG. 1 that were discovered and aredisclosed herein. The legend for FIG. 2 is as follows:

-   -   ^(a) Starting material: Form HCl1 or amorphous material (Am)        obtained by freeze-drying.    -   ^(b) Occ: the total occurrence included 216 experiments carried        out in Phase 2 (described in Example 1 herein) for which 39        samples were analyzed additionally wet or the mother liquor was        evaporated and analyzed giving a total of 254 materials        characterized. For example, “(3, 1.2%)” correspond to 3        occurrences of the form out of 254 measurements, giving a        percentage of 1.2%. For 62 out of the 254 measurements (9%), the        product yield was too low to identify the solid form, or the        materials were wet.    -   ^(d) Am: amorphous form.

FIG. 3 is a characteristic X-ray powder diffraction (XRPD) pattern oftwo batches of Form A of ponatinib hydrochloride in which the data foreach batch was acquired prior to and after DVS humidity cycling.Relative Intensity (in counts) is shown on the vertical axis and thedegrees (2θ) is shown on the horizontal axis.

FIG. 4 is a characteristic X-Ray Powder Diffraction (XRPD) patternobtained from Form A of ponatinib hydrochloride. Relative Intensity (incounts) is shown on the vertical axis and the degrees (2θ) is shown onthe horizontal axis.

FIG. 5 is a characteristic differential scanning calorimetry (DSC) scanobtained from Form A of ponatinib hydrochloride. Heat flow [mW] is shownon the vertical axis and temperature (° C.) is shown on the horizontalaxis.

FIG. 6 is a characteristic thermogravimetric analysis (TGA) andthermogravimetric analysis with mass spectroscopic analysis of volatiles(TGMS) scan obtained from Form A of ponatinib hydrochloride.

FIG. 7 is a characteristic ¹H-NMR Spectrum (600 MHz) of ponatinibhydrochloride in solution obtained from Form A of ponatinibhydrochloride in DMSO-d₆ at 300 K. Normalized Intensity is shown on thevertical axis and chemical shift (ppm) is shown on the horizontal axis.

FIG. 8 is a characteristic ¹⁹F-NMR Spectrum (564 MHz) of ponatinibhydrochloride in solution obtained from Form A of ponatinibhydrochloride in DMSO-d₆ at 300 K. Normalized Intensity is shown on thevertical axis and chemical shift (ppm) is shown on the horizontal axis.

FIG. 9 is a characteristic ¹³C-NMR Spectrum (151 MHz) of ponatinibhydrochloride in solution obtained from Form A of ponatinibhydrochloride in DMSO-d₆ at 300 K. Normalized Intensity is shown on thevertical axis and chemical shift (ppm) is shown on the horizontal axis.

FIG. 10 is a characteristic mass spectral pattern obtained from Form Aof ponatinib hydrochloride in which the top mass spectral pattern is theobserved mass of Form A and the bottom mass spectral pattern is adaughter ion spectrum of the parent shown above of Form A. Relativeabundance is shown on the vertical axis and atomic weight (m/z) is shownon the horizontal axis.

FIG. 11 is a characteristic mass spectral fragmentation pattern of FormA of ponatinib hydrochloride. Relative abundance is shown on thevertical axis and atomic weight (m/z) is shown on the horizontal axis.

FIG. 12 shows the structure of Form A of ponatinib hydrochloride inaccordance with the data presented in the table herein designated as“Crystal Data and Structure Refinement for Ponatinib Hydrochloride FormA.” Atoms in this FIG. 12 are color coded according to atom type:carbon, grey; nitrogen, blue; oxygen, red; hydrogen, white; fluorine,yellow; chlorine, green.

FIG. 13 is a characteristic FT-IR spectrum obtained from Form A ofponatinib hydrochloride. Percent transmittance (%) is shown on thevertical axis and wavenumber (cm⁻¹) is shown on the horizontal axis.

FIG. 14 is a characteristic HPLC spectrum obtained from Form A ofponatinib hydrochloride. Absorbance units are shown on the vertical axis(mAU) and time (minutes) is shown on the horizontal axis.

FIG. 15 is a characteristic X-Ray Powder Diffraction (XRPD) patternobtained from Form A of ponatinib hydrochloride (bottom) as comparedagainst a XRPD pattern of Form B (middle) and Form C (top). RelativeIntensity (in counts) is shown on the vertical axis and the degrees (2θ)is shown on the horizontal axis.

FIG. 16 is a characteristic HPLC spectrum obtained from Form B ofponatinib hydrochloride. Absorbance units are shown on the vertical axis(mAU) and time (minutes) is shown on the horizontal axis.

FIG. 17 is a characteristic X-Ray Powder Diffraction (XRPD) patternobtained from Form C of ponatinib hydrochloride (top) as comparedagainst a XRPD pattern of Form A (bottom). Relative Intensity (incounts) is shown on the vertical axis and the degrees (2θ) is shown onthe horizontal axis.

FIG. 18 is a characteristic differential scanning calorimetry (DSC) scanobtained from Form C of ponatinib hydrochloride. Heat flow [mW] is shownon the vertical axis and temperature (° C.) is shown on the horizontalaxis.

FIG. 19 is a characteristic thermogravimetric analysis (TGA) scanobtained from Form C of ponatinib hydrochloride.

FIG. 20 is a characteristic TGMS thermogram obtained from Form C ofponatinib hydrochloride.

FIG. 21 is a characteristic HPLC spectrum obtained from Form C ofponatinib hydrochloride. Absorbance units are shown on the vertical axis(mAU) and time (minutes) is shown on the horizontal axis.

FIG. 22 is a characteristic X-Ray Powder Diffraction (XRPD) patternobtained from Form D of ponatinib hydrochloride as compared against aXRPD pattern of Form A and certain other crystalline forms within theclass of HCl3. Relative Intensity (in counts) is shown on the verticalaxis and the degrees (2θ) is shown on the horizontal axis.

FIG. 23 is a characteristic differential scanning calorimetry (DSC) scanobtained from Form D of ponatinib hydrochloride. Heat flow [mW] is shownon the vertical axis and temperature (° C.) is shown on the horizontalaxis.

FIG. 24 is a characteristic thermogravimetric analysis (TGA) scanobtained from Form D of ponatinib hydrochloride.

FIG. 25 is a characteristic FT-IR spectrum obtained from Form D ofponatinib hydrochloride. Percent transmittance (%) is shown on thevertical axis and wavenumber (cm⁻¹) is shown on the horizontal axis. TheForm A starting material is shown in red and Form D (PSM1) is shown inblue.

FIG. 26 is a characteristic HPLC spectrum obtained from Form D ofponatinib hydrochloride. Absorbance units are shown on the vertical axis(mAU) and time (minutes) is shown on the horizontal axis.

FIG. 27 is a characteristic X-Ray Powder Diffraction (XRPD) patternobtained from Form F of ponatinib hydrochloride as compared against aXRPD pattern of Form A and certain other crystalline forms within theclass of HCl5. Relative Intensity (in counts) is shown on the verticalaxis and the degrees (2θ) is shown on the horizontal axis.

FIG. 28 shows two characteristic differential scanning calorimetry (DSC)scans obtained from Form F of ponatinib hydrochloride. The top scan isthe DSC curve of VDS1. The bottom scan is the DSC curve of VDS2. Heatflow [mW] is shown on the vertical axis and temperature (° C.) is shownon the horizontal axis.

FIG. 29 is a characteristic overlay of thermogravimetric analysis andSDTA (top) and TGMS (bottom) scan obtained from Form F of ponatinibhydrochloride (VDS1).

FIG. 30 is a characteristic overlay of thermogravimetric analysis (top)and TGMS (bottom) scan obtained from Form F of ponatinib hydrochloride(VDS2).

FIG. 31 is a characteristic FT-IR spectrum obtained from Form F ofponatinib hydrochloride. Percent transmittance (%) is shown on thevertical axis and wavenumber (cm⁻¹) is shown on the horizontal axis. TheForm A starting material is shown in red and Form F (VDS1) is shown ingreen.

FIG. 32 is a characteristic FT-IR spectrum obtained from Form F ofponatinib hydrochloride. Percent transmittance (%) is shown on thevertical axis and wavenumber (cm⁻¹) is shown on the horizontal axis. TheForm A starting material is shown in purple and Form F (VDS2) is shownin red.

FIG. 33 is a characteristic HPLC spectrum obtained from Form F ofponatinib hydrochloride (VDS2). Absorbance units are shown on thevertical axis (mAU) and time (minutes) is shown on the horizontal axis.

FIG. 34 is a characteristic X-Ray Powder Diffraction (XRPD) patternobtained from Form H of ponatinib hydrochloride as compared against aXRPD pattern of Form A (bottom) and certain other crystalline formswithin the class of HCl6. Relative Intensity (in counts) is shown on thevertical axis and the degrees (2θ) is shown on the horizontal axis.

FIG. 35 shows two characteristic differential scanning calorimetry (DSC)scans obtained from Form H of ponatinib hydrochloride. The top scan isthe DSC curve of VDS3. The bottom scan is the DSC curve of VDS4. Heatflow [mW] is shown on the vertical axis and temperature (° C.) is shownon the horizontal axis.

FIG. 36 is a characteristic overlay of thermogravimetric analysis (top)and TGMS (bottom) scan obtained from Form H of ponatinib hydrochloride(VDS3).

FIG. 37 is a characteristic overlay of thermogravimetric analysis (top)and TGMS (bottom) scan obtained from Form H of ponatinib hydrochloride(VDS4).

FIG. 38 is a characteristic FT-IR spectrum obtained from Form H ofponatinib hydrochloride. Percent transmittance (%) is shown on thevertical axis and wavenumber (cm⁻¹) is shown on the horizontal axis. TheForm A starting material is shown in purple and Form H (VDS3) is shownin red.

FIG. 39 is a characteristic FT-IR spectrum obtained from Form H ofponatinib hydrochloride. Percent transmittance (%) is shown on thevertical axis and wavenumber (cm⁻¹) is shown on the horizontal axis. TheForm A starting material is shown in purple and Form H (VDS4) is shownin red.

FIG. 40 is a characteristic HPLC spectrum obtained from Form H ofponatinib hydrochloride (VDS4). Absorbance units are shown on thevertical axis (mAU) and time (minutes) is shown on the horizontal axis.

FIG. 41 is an overlay of characteristic X-Ray Powder Diffraction (XRPD)patterns for each of the solid forms identified in FIG. 1 where thevertical axis denotes relative intensity (counts) and the horizontalaxis denotes Two Theta (Degrees). From the bottom to the top of thisfigure the following solid forms and solvents are as follows: thestarting material ponatinib HCl (HCl1) (Form A), Form HCl2 (QSA12.1,solvent: water) (Form B), Form HCl2b (QSA21.1, solvent: water) (Form C),Form HCl3-class (GRP12.1, solvent: toluene) (Form D), mixture HCl1+HCl4(GRP1.1, solvent: hexafluorobenzene) (Form E), Form HCl5 (VDS28.1,solvent: butylacetate) (Form F), Form HCl5b (VDS28.2 after drying,solvent: butylacetate) (Form G) and HCl6-class (VDS6.1, solvent:methanol) (Form H).

FIG. 42 shows representative digital images of (from top to bottom, leftto right): HCl6-class (VDS6.1, vds050.0c:E1), Form HCl5 (VDS28.1,vds05.0c:B3), Form HCl5b (VDS28.2, vds05.1c:B6), mixture HCl1+HCl4(GRP1.1, grp02.0c:A1), Form HCl3-class (GRP12.1, grp02.1c:L1), Form HCl2(QSA12.1, qsa00.1c:A2) and Form HCl2b (QSA21.1, qsa00.1c:J2).

FIG. 43 is a characteristic X-Ray Powder Diffraction (XRPD) patternobtained from Form J of ponatinib hydrochloride. Relative Intensity (incounts) is shown on the vertical axis and degrees (2θ) shown on thehorizontal axis.

FIG. 44 is a characteristic X-Ray Powder Diffraction (XRPD) patternobtained from Form K of ponatinib hydrochloride. Relative Intensity (incounts) is shown on the vertical axis and degrees (2θ) shown on thehorizontal axis.

FIG. 45 shows characteristic XRPD patterns of Form A of ponatinibhydrochloride (bottom pattern) and amorphous ponatinib hydrochloride(top pattern) (solvent: 2,2,2-trifluroethanol) where the vertical axisdenotes relative intensity (counts) and the horizontal axis denotes TwoTheta (Degrees).

FIG. 46 is a characteristic Differential Scanning calorimetry (DSC)thermogram of amorphous3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemono hydrochloride. An intense endothermic event with a peak of 259.4°C. was observed, corresponding to the melting point of the amorphousform. The vertical axis denotes Heat Flow [mW] and the horizontal axisdenotes Temperature (° C.).

FIG. 47 is a characteristic HPLC spectrum obtained from Form H ofponatinib hydrochloride (VDS4). Absorbance units are shown on thevertical axis (mAU) and time (minutes) is shown on the horizontal axis.Absorbance units are shown on the vertical axis (mAU) and time (minutes)is shown on the horizontal axis.

FIG. 48 is a tabular summary of solid forms of ponatinib that includepolymorphs and pseudo-polymorphs identified as Forms A through J.

FIG. 49 is a tabular summary of occurances, crystallization methods,physical forms, endotherms and purities of ponatinib polymorphs andpseudo-polymorphs identified as Forms A through J.

FIG. 50 shows the molecular structure and numbering scheme of ponatinibfree base crystalline Form A (anhydrate) determined by single-crystalX-ray analysis.

FIG. 51 shows XRPD patterns for ponatinib free base crystalline Form A(anhydrate) simulated and experimentally obtained.

FIG. 52 is a characteristic differential scanning calorimetry (DSC) scanobtained from crystalline Form A of ponatinib free base (anhydrate).Heat flow [mW] is shown on the vertical axis and temperature (° C.) isshown on the horizontal axis.

FIG. 53 shows the molecular structure and numbering scheme of B-Classponatinib/1,4-dioxane (1:1) solvate (Form B) determined bysingle-crystal X-ray analysis.

FIG. 54 is a simulated XRPD pattern for B-Class ponatinib/1,4-dioxane(1:1) solvate (Form B).

FIG. 55 shows the molecular structure and numbering scheme of B-Classponatinib/perfluorobenzene (1:1) solvate (Form B) determined bysingle-crystal X-ray analysis.

FIG. 56 is the XRPD patterns for B-Class ponatinib/perfluorobenzene(1:1) solvate (Form B) simulated and experimentally obtained.

FIG. 57 shows XRPD patterns for Form B ponatinib/2-methylTHF (1:0.4)solvate (upper pattern); Form B ponatinib/cyclohexanone (1:1) solvate(middle pattern); and Form A (bottom pattern).

FIG. 58 is a characteristic differential scanning calorimetry (DSC) scanobtained from B-Class 1:1 ponatinib/cyclohexanone solvate (QSA7.1). Heatflow [mW] is shown on the vertical axis and temperature (° C.) is shownon the horizontal axis.

FIG. 59 is a characteristic overlay of TGA and SDTA thermograms ofB-Class 1:1 ponatinib/cyclohexanone solvate (QSA7.1).

FIG. 60 is a characteristic differential scanning calorimetry (DSC) scanobtained from B-Class 1:0.4 ponatinib/2-methylTHF solvate (GEN8.1). Heatflow [mW] is shown on the vertical axis and temperature (° C.) is shownon the horizontal axis.

FIG. 61 is a characteristic overlay of TGA and SDTA thermograms ofB-Class 1:0.4 ponatinib/2-methylTHF solvate (GEN8.1).

FIG. 62 is a characteristic differential scanning calorimetry (DSC) scanobtained from ponatinib low crystalline Form C (GEN3.1). Heat flow [mW]is shown on the vertical axis and temperature (° C.) is shown on thehorizontal axis.

FIG. 63 is a characteristic overlay of TGA and SDTA thermograms ofponatinib low crystalline Form C (GEN3.1).

FIG. 64 shows XRPD patterns for ponatinib low crystalline Form C(GEN3.1) (top pattern) and Form A (bottom pattern).

FIG. 65 is a characteristic differential scanning calorimetry (DSC) scanobtained from Form D (GEN5.1R1) of ponatinib. Heat flow [mW] is shown onthe vertical axis and temperature (° C.) is shown on the horizontalaxis.

FIG. 66 is a characteristic overlay of TGA and SDTA thermograms of FormD (GEN5.1R1) of ponatinib.

FIG. 67 shows XRPD patterns for Form D of ponatinib (middle pattern) andForm A (bottom pattern). Also shown is the XRPD pattern for a mixture ofB-Class solvates and Form D of ponatinib (upper pattern).

FIG. 68 is a characteristic differential scanning calorimetry (DSC) scanobtained from E-Class ponatinib/THF 1:1 solvate (GEN7.1). Heat flow [mW]is shown on the vertical axis and temperature (° C.) is shown on thehorizontal axis.

FIG. 69 is a characteristic overlay of TGA and SDTA thermograms ofE-Class ponatinib/THF 1:1 solvate (GEN7.1).

FIG. 70 shows XRPD patterns for E-Class ponatinib/THF 1:1 solvate(GEN7.1) (upper pattern); E-Class ponatinib/chloroform solvate (SLP3.1)(middle pattern); and Form A (bottom pattern).

FIG. 71 is a characteristic overlay of TGA and SDTA thermograms ofponatinib Form F (AS16.2).

FIG. 72 a characteristic differential scanning calorimetry (DSC) scanobtained from Form H (VLD1, dried solid from stock). Heat flow [mW] isshown on the vertical axis and temperature (° C.) is shown on thehorizontal axis.

FIG. 73 is a characteristic overlay of TGA and SDTA thermograms of FormH (VLD1, dried solid from stock).

FIG. 74 shows a series of XRPD patterns as follows: Plot 1 is Form H(VLD2 experiment, after 2-weeks and drying); Plot 2 is Form H (VLD1experiment, after 2-weeks and drying); Plot 3 is Form H (VLD1experiment, dried solid from stock after DVS); Plot 4 is Form H (VLD1,dried solid from stock); Plot 5 is Form H (VLD19); and the bottom plotis the XRPD for Form A.

FIG. 75 is a characteristic FT-IR spectrum obtained from Form H ofponatinib overlaid with the FT-IR spectrum obtained for Form A. Percenttransmittance (%) is shown on the vertical axis and wavenumber (cm⁻¹) isshown on the horizontal axis.

FIG. 76 is a characteristic FT-IR spectrum obtained from Form H ofponatinib overlaid with the FT-IR spectrum obtained for Form A, for theregion of wavelength 1750-600 nm. Percent transmittance (%) is shown onthe vertical axis and wavenumber (cm⁻¹) is shown on the horizontal axis.

FIG. 77 is a characteristic differential scanning calorimetry (DSC) scanobtained for Form I (GEN9.1). Heat flow [mW] is shown on the verticalaxis and temperature (° C.) is shown on the horizontal axis.

FIG. 78 is a characteristic overlay of TGA and SDTA thermograms of FormI (GEN9.1).

FIG. 79 shows XRPD patterns for ponatinib Form I (upper pattern) andForm A (bottom pattern) in overlay.

FIG. 80 shows an overlay of XRPD patterns as follows: Plot 6 is the XRPDpattern for Form A (VDS2, after stability study); Plot 7 is the XRPDpattern for Form J (VDS2); Plot 8 is the XRPD pattern for Form J (VDS10of screen S10010A); and Plot 9 is another XRPD pattern of ponatinib FormA.

FIG. 81 shows a characteristic FT-IR spectrum obtained from Form J inoverlay with the FT-IR spectrum obtained for Form A. Percenttransmittance (%) is shown on the vertical axis and wavenumber (cm⁻¹) isshown on the horizontal axis.

FIG. 82 shows a characteristic FT-IR spectrum obtained from Form J inoverlay with the FT-IR spectrum obtained for Form A, for the region ofwavelength 1750-600 nm. Percent transmittance (%) is shown on thevertical axis and wavenumber (cm⁻¹) is shown on the horizontal axis.

FIG. 83 shows an overlay of the XRPD results obtained for selectedponatinib free base polymorphs (from bottom to top): Form A (SM);B-Class (QSAS7.1); Form C, low crystalline (GEN3.1); Form D (GEN5.1);E-Class (SLP3.1); Form F (SLP10.1); Form G (AS19.1); Form H (VDL19.1);Form I, low crystalline (GEN9.1); and Form J, low crystalline (VDS10.1).

FIG. 84 shows an overlay of the XRPD patterns of the free base startingmaterial, with the two patterns representing the two batches (F09-05575:lower pattern; and F09-05576: upper pattern).

FIG. 85 is a characteristic differential scanning calorimetry (DSC) scanobtained for ponatinib free base starting material batch F09-05575. Heatflow [mW] is shown on the vertical axis and temperature (° C.) is shownon the horizontal axis.

FIG. 86 is a characteristic differential scanning calorimetry (DSC) scanobtained for ponatinib free base starting material batch F09-05576. Heatflow [mW] is shown on the vertical axis and temperature (° C.) is shownon the horizontal axis.

FIG. 87 is a characteristic overlay of TGA and SDTA thermograms ofponatinib free base starting material batch F09-05575.

FIG. 88 is a characteristic overlay of TGA and SDTA thermograms ofponatinib free base starting material batch F09-05576.

FIG. 89 is a tabular summary of the physical stability of several of theponatinib solid forms.

FIG. 90 is a tabular summary of the results from the scale-upexperiments for selected free base forms.

FIG. 91 is a tabular summary of various characterizations of ponatinibfree base forms reproduced at the 120 mg scale.

DETAILED DESCRIPTION OF THE INVENTION

It was discovered that both3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamideand3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemono hydrochloride can be obtained in various solid state crystallineforms.

The terms “crystalline form” or “polymorphic form” or “polymorph” may beused interchangeably herein, and refer to a crystalline form of pontinibor ponatinib hydrochloride that is distinct from the amorphous form ofponatinib or ponatinib hydrochloride or other form(s) of ponatinib orponatinib hydrochloride as determined by certain physical propertiessuch thermodynamic stability, physical parameters, x-ray structure, DSCand preparation processes.

While polymorphism classically refers to the ability of a compound tocrystallize into more than one distinct crystal species (havingidentical chemical structure but quite different physicochemicalproperties), the term “pseudopolymorphism” is typically applied tosolvate and hydrate crystalline forms. For purposes of this disclosure,however, both true polymorphs as well as pseudopolymorphs, (i.e.,hydrate and solvate forms), are included in the scope of the term“crystalline forms” and “polymorphic forms.” In addition, “amorphous”refers to a disordered solid state.

It should be noted that different samples of a particular crystallineform may share the same major XRPD peaks, but that there can bevariation in XRPD patterns with regard to the minor peaks. In regards toXRPD, the term “about,” when used in relation to XRPD maxima values (indegrees two theta), generally means within 0.3 degrees two theta of thegiven value. Alternatively, the term “about” can mean (in this and allcontexts) a value falls within an accepted standard of error of the meanwhen considered by one of ordinary skill in the art. As used herein, theterms “isolated” and “substantially pure” mean that more than about 50%of crystalline ponatinib or ponatinib hydrochloride is present (as canbe determined by a method in accordance with the art) in the identifiedcrystalline form relative to the sum of other solid form(s) present inthe selected material.

Definitions and Abbreviations Solvent Abbreviation

-   -   DCM Dichloromethane    -   DMA N,N-Dimethylacetamide    -   DMF N,N-Dimethylformamide    -   DMSO Dimethylsulfoxide    -   TFE 2,2,2-Trifluoroethanol    -   THF Tetrahydrofuran    -   2-methylTHF 2-Methyltetrahydrofuran    -   EtOH Ethanol    -   MeOH Methanol

Other Abbreviations (Alphabetical Order)

-   -   Am Amorphous    -   API Active Pharmaceutical Ingredient    -   AS Anti-solvent    -   CI Counter-ion    -   DSC Differential Scanning calorimetry    -   DVS Dynamic Vapor Sorption    -   GRP ID for Grinding experiment    -   HPLC High-Performance Liquid Chromatography    -   HT-XRPD High Throughput X-Ray Powder Diffraction    -   HR-XRPD High Resolution X-Ray Powder Diffraction    -   LC Low Crystalline material    -   MS Mass Spectroscopy    -   PSM ID for Cooling/evaporative crystallization experiment    -   SAS Solubility assessment    -   SDTA Single Differential Thermal Analysis    -   S Solvent    -   SM Starting material    -   TGA Thermogravimetric Analysis    -   TGMS Thermogravimetric Analysis coupled with Mass Spectroscopy    -   VDL ID for Vapor diffusion into liquids experiments    -   VDS ID for Vapor diffusion onto solids experiments    -   XRPD X-Ray Powder Diffraction

Analytical Methods X-Ray Powder Diffraction

XRPD patterns were obtained using an Avantium T2 high-throughput XRPDset-up. The plates were mounted on a Bruker GADDS diffractometerequipped with a Hi-Star area detector. The XRPD platform was calibratedusing Silver Behenate for the long d-spacings and Corundum for the shortd-spacings.

Data collection was carried out at room temperature using monochromaticCuK_(α) radiation in the 2θ region between 1.5° and 41.5°, which is themost distinctive part of the XRPD pattern. The diffraction pattern ofeach well was collected in two 2θ ranges (1.5°≦2θ≦21.5° for the firstframe, and 19.5°≦2θ≦41.5° for the second) with an exposure time of 90seconds for each frame. No background subtraction or curve smoothing wasapplied to the XRPD patterns. The carrier material used during XRPDanalysis was transparent to X-rays and contributed only slightly to thebackground.

Thermal Analysis

Melting properties were obtained from DSC thermograms, recorded with aheat flux DSC822e instrument (Mettler-Toledo GmbH, Switzerland). TheDSC822e was calibrated for temperature and enthalpy with a small pieceof indium (m.p.=156.6° C.; ΔHf=28.45 J·g⁻¹). Samples were sealed instandard 40 μl aluminum pans, pin-holed and heated in the DSC from 25°C. to 300° C., at a heating rate of 10° C. min⁻¹. Dry N₂ gas, at a flowrate of 50 ml min⁻¹ was used to purge the DSC equipment duringmeasurement.

Mass loss due to solvent or water loss from the various crystal sampleswas determined by TGA/SDTA. Monitoring the sample weight, during heatingin a TGA/SDTA851e instrument (Mettler-Toledo GmbH, Switzerland),resulted in a weight vs. temperature curve. The TGA/SDTA851e wascalibrated for temperature with indium and aluminum. Samples wereweighed into 100 μl aluminum crucibles and sealed. The seals werepin-holed and the crucibles heated in the TGA from 25 to 300° C. at aheating rate of 10° C. min⁻¹. Dry N₂ gas was used for purging.

The gases evolved from the TGA samples were analyzed by a massspectrometer Omnistar GSD 301 T2 (Pfeiffer Vacuum GmbH, Germany). Thelatter is a quadrupole mass spectrometer which analyses masses in therange of 0-200 amu.

Digital Imaging

Digital images were automatically collected for all the wells of eachwell-plate, employing a Philips PCVC 840K CCD camera controlled byAvantium Photoslider software.

Press

For the compression tests, an Atlas Power Press T25 (Specac) was used.The Atlas Power T25 is a power assisted hydraulic press operating up to25 Tons.

HPLC Analytical Method

HPLC analysis was performed using an Agilent 1200SL HPLC system equippedwith UV and MS detectors following the conditions presented below:

HPLC Equipment: LC-MS Manufacturer: Agilent HPLC: HP1200sl UV-detector:HP DAD MS-detector: HP1100 API-ES MSD VL-type Column: Waters Sunfire C18(100 × 4.6 mm; 3.5 μm). Column temp: 35° C. Mobile phase: Gradient modeMobile phase A: 1000/1; H₂O/TFA (v/v) Mobile phase B: 1000/1;ACN/TFA(v/v) Flow: 1.0 ml/min Gradient program: Time [min]: % A: % B:  090 10 15 20 80 16 90 10 18 90 10 Posttime: 1 UV-Detector: DAD Range:200-400 nm Wavelength: 260 nm Slit Width: 4 nm Time: 0-17 minMS-Detector: MSD Scan: positive Mass Range: 70-1000 amu Fragmentator: 70Time: 0-17 min Autosampler: Temperature: Not controlled Injection mode:loop Injection volume: 5 μl Needle wash: 2/3; ACN/H₂O (v/v) Dilutionsolvent: 2,2,2-Trifluoroethanol

The compound integrity is expressed as a peak-area percentage,calculated from the area of each peak in the chromatogram, except the‘injection peak’, and the total peak-area, as follows:

${{peak} - {{area}\mspace{14mu} \%}} = {\frac{{peak} - {area}}{{total} - {area}}*100\%}$

The peak-area percentage of the compound of interest is employed as anindication of the purity of the component in the sample.

I. Polymorphic Forms of Ponatinib Mono Hydrochloride

Through XRPD analysis, a total of eleven polymorphic forms of ponatinibhydrochloride were discovered. Each of the eleven new polymorphic formsare referred to herein as: HCl1 (also referred to herein as “Form A”),HCl2 (also referred to herein as “Form B”), HCl2b (also referred toherein as “Form C”), HCl3-class (also referred to herein as “Form D”), amixture HCl1+HCl4 (also referred to herein as “Form E”), HCl5-class orsimply HCl5 (also referred to herein as “Form F”), HCl5b or HCl5desolvate (also referred to herein as “Form G”), HCl6-class (alsoreferred to herein as “Form H”), HCl6 desolvate (also referred to hereinas “Form I”), HCl7 (also referred to herein as “Form J”), and HCl8 (alsoreferred to herein as “Form K”). The nature or origin of these elevenpolymorphic forms is indicated in FIG. 1. In addition, certaincharacteristics of the referenced polymorphic forms are provided as wellin FIG. 2. For instance, Form A is indicated as being an anhydrate ofponatinib hydrochloride and additionally was obtained as a singlecrystal.

In general, crystalline forms of ponatinib hydrochloride have physicalproperties (such as high stability, etc.) that are advantageous for thecommercial preparation of solid dosage forms as compared to amorphousponatinib hydrochloride. The distinction between crystalline ponatinibhydrochloride and amorphous ponatinib hydrochloride can be readily seenwith the same type of physical chemical data (e.g., DSC, XRPD, thermalanalysis) that is used to distinguish the individual crystalline formsof ponatinib hydrochloride disclosed herein.

With reference to the foregoing methodologies, attention is now drawn toeach of the discovered polymorphs of3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemono hydrochloride.

Characteristics of Form A (HCl1):

The anhydrate HCl1 (same crystalline form as the starting material) wasthe predominant crystalline form discovered. The chemical structure ofponatinib hydrochloride has been unambiguously established by acombination of nuclear magnetic resonance spectroscopy (NMR), massspectrometry (MS), and single crystal X-ray crystallography withconfirmatory data from elemental and chloride analysis, Fouriertransform infra-red (FT-IR) spectroscopy, and ultraviolet (UV)spectroscopy. The preferred solid form of ponatinib hydrochloride is theanhydrous crystalline HCl-1 solid form or Form A.

With reference to FIG. 3, samples of Ponatinib HCl, ASI Batch 110020 andCGAM Batch F08-06057 were analyzed by X-ray powder diffraction (XRPD).In each case, the material was analyzed prior to and after DVS humiditycycling. XRPD patterns were obtained using a high-throughput XRPDdiffractometer. Data collection was carried out at room temperatureusing monochromatic CuK_(α) radiation in the 2θ region between 1.5° and41.5°, which is the most distinctive part of the XRPD pattern. Thediffraction pattern of each well was collected in two 2θ ranges(1.5°≦2θ≦21.5° for the first frame, and 19.5°≦2θ≦41.5° for the second)with an exposure time of 90 seconds for each frame. No backgroundsubtraction or curve smoothing was applied to the XRPD patterns. FIG. 3shows the X-ray powder diffraction pattern of these materials, each inthe HCl-1 solid form. This powder pattern is consistent with the powderpattern simulated from single crystal X-ray diffraction experiments onthe HCl-1 form. XRPD data acquired prior to, and after DVS humiditycycling experiments, indicates that the HCl-1 solid form is maintainedafter humidity cycling. In the XRPD pattern of Form A shown in FIG. 3,at least one or all of the following peaks in degrees two theta (2θ) isshown: 5.9; 7.1; 10.0; 12.5; 16.4; 19.3; 21.8; 23.8; and 26.1. Incertain embodiments, the XRPD pattern of Form A shows two peaks, threepeaks, four peaks or five peaks. The term “about” applies to each listedpeak for this and all other forms mentioned in this disclosure.

FIG. 4 shows a characteristic X-Ray Powder Diffraction (XRPD) patternfor Form A of ponatinib hydrochloride in which greater detail relativeto the XRPD is seen. The XRPD pattern of Form A shown in FIG. 4 shows atleast one or more of the following peaks in degrees two theta (2θ): 5.9;7.1; 10.0; 12.5; 13.6; 14.1; 15.0; 16.4; 17.7; 18.6; 19.3; 20.4; 21.8;22.3; 23.8; 24.9; 26.1; 27.0; 28.4; 30.3; 31.7; and 35.1. In certainembodiments, Form A is characterized by a XRPD pattern comprising one ormore of the following peaks two theta (2θ): 12.5; 19.3; 23.8; and 26.1.In certain embodiments, the XRPD pattern of Form A shows two peaks,three peaks, four peaks or five peaks.

In differential vapor sorption (DVS) experiment with HCl-1, the relativehumidity was cycled from 45% to 95% (sorption), to 0% (desorption) andback to 45% (sorption) at a constant temperature of 25° C., with a holdtime of 60 minutes per step. The results of this DVS experiment onponatinib HCl CGAM Batch F08-060507 exhibited a 1.1% water uptake at 95%humidity, and ponatinib HCl ASI Batch 110020 exhibited a 1.4% wateruptake at a relative humidity of 95%. This water uptake was reversibleon cycling to lower humidity. These results demonstrate that HCl-1 isnot a hygroscopic compound. The effect of the humidity cycling on HCl-1was also assessed by X-ray powder diffraction (XRPD) analysis before andafter the DVS experiment. The XRPD data revealed that humidity cyclinghad no effect on the solid form of the material, which remained in theHCl-1 solid form.

With reference to FIG. 5, the melting point of ponatinib HCl in theHCl-1 solid form, was determined by differential scanning calorimetry(DSC). The sample of ponatinib HCl, ASI Batch 110020, was analyzed in apin-holed crucible in the temperature range of 25° C. to 300° C. at aheating rate of 10° C. per minute using dry N₂ gas purge. An intenseendothermic event with a peak of 264.1° C. was observed, correspondingto the melting point of Form A.

With reference to FIG. 6, Thermogravimetric analysis (TGA) andthermogravimetric analysis with mass spectroscopic analysis of volatiles(TGMS) was performed on ponatinib HCl, ASI Batch 110020. The sample,contained in a pin-holed crucible, was heated in the TGA instrument from25° C. to 300° C. at a heating rate of 10° C. min-1, with dry N₂ gasused for purging. Gases evolved from the TGA were analyzed using aquadrupole mass spectrometer. Ponatinib HCl, ASI Batch 110020, in theHCl-1 solid form, contained 0.31% water by weight and 0.85% ethanol byweight at the time of release. The TGA/TGMS experiment indicated thatmass losses of 0.2% (water) and 0.6% (ethanol, from the crystallizationsolvent) are observed between the temperature range of 25−130° C. and130-240° C., respectively. These losses are consistent with the waterand ethanol content at the time of release. Ethanol is released from thematerial at a higher temperature than water, although not associatedwith ponatinib HCl in the HCl-1 solid form as a solvate.

Extensive solution phase NMR studies using a combination of multiple 1Dand 2D NMR methods were performed on Form A of ponatinib HCl to obtain acomplete assignment of ¹H, ¹⁹F, and ¹³C resonances, and hence to confirmthe chemical structure of ponatinib HCl. Analyses were performed atARIAD Pharmaceuticals, Inc., Cambridge, Mass., on a sample of ponatinibHCl (ASI Batch 110020) dissolved in deuterated DMSO (DMSO-d₆) solvent.NMR spectra were acquired at a temperature of 300 K on a Bruker AvanceIII-600 MHz NMR spectrometer equipped with a 5 mm BBFO z-gradient probe.All ¹H chemical shifts were referenced to the DMSO peak at 2.5 ppm. Withreference to FIG. 7, the 1D ¹H-NMR spectra of Form A of ponatinib HCl inDMSO-d₆ is shown. ¹H resonance 32a arises from the protonated piperazinemoiety in ponatinib HCl. The EtOH resonances appearing in both ¹H (FIG.7) and ¹³C spectra (FIG. 9) arise from residual EtOH present inponatinib HCl. FIG. 8 shows the 1D ¹⁹F-NMR spectra of Form A ofponatinib HCl in DMSO-d₆ with a characteristic chemical shift at 57.94ppm. FIG. 9 shows the 1D ¹³C-NMR spectra of Form A of ponatinib HCl inDMSO-d₆.

Table 1 summarizes the relevant chemical shift data of ponatinib monohydrochloride Form A obtained from the ¹H and ¹³C-NMR experiments. Thenumber of signals and their relative intensity (integrals) confirm thenumber of protons and carbons in the structure of Form A of ponatinibHCl. These chemical shift data are reported in according to the atomnumbering scheme shown immediately below:

TABLE 1 ¹H and ¹³C Chemical Shift Data (in ppm) of Form A of ponatinibHCl, in DMSO-d₆ at 300 K. Atom Number Group ¹H, ppm ¹³C, ppm Integral ¹HMultiplicity, Hz ¹³C Multiplicity, Hz  3 CH 8.72 145.03 0.98  m¹  4 CH7.39 119.05 1.02  dd² (J = 9.2, 4.4)  5 CH 8.25 126.06  ND⁷ m  6 C —139.63 — —  8 CH 8.22 138.2 ND m  9 C — 111.69 — — 10 C — 81.11 — — 11 C— 96.38 — — 12 C — 121.76 — — 13 C — 143.52 — — 14 CH 7.54 130.03 1.01d³ (J = 8.1)  15 CH 7.98 128.49 1.02  dd (J = 8, 1.4) 16 C — 132.12 — —17 CH 8.22 130.19 ND m 18 CH₃ 2.6  20.36 3.09  s⁴ 19 C — 164.63 — — 21NH 10.65  — 1.03 s 22 C — 138.53 — — 23 CH 8.13 123.54 1.02 d (J = 8.4)24 CH 7.71 131.42 1.01 d (J = 8.4) 25 C — 130.95 — — 26 C — 127.53 — —q⁶ (J = 29.7) 27 CH 8.25 117.42 ND m q (J = 6.2)  28 CH₂ 3.66 56.56 2.01s — 35 C — 124.25 — —   q (J = 272.9) 37 CH₃ 2.74 41.96 3.07 s 30, 34⁸CH₂ 2.87 49.16 1.76 m 30′, 34′⁸ CH₂ 2.52 49.16 ND m 31, 33⁸ CH₂ 3.0252.53 1.78 m 31′, 33′⁸ CH₂ 3.35 52.53 — — 32a NH 10.85  — 0.74 br. s.⁵36, 38, 39 CF₃ ¹⁹F: −57.9 — — — m: multiplet dd: doublet of doublets d:doublet s: singlet br. s: broad singlet q: quartet ND: not determineddue to spectral overlap in the ¹H NMR spectrum. Due to symmetry, theresonance pair 30 and 34 as well as the resonance pair 31 and 33 havedegenerate chemical shifts. In addition the methylene protons of theseresonances appear as diastereotopic pairs.

With reference to FIG. 10, mass spectral experiments and collisionallyactivated MS2 fragmentation of Form A of ponatinib HCl were carried outusing Thermo Finnegan Exactive accurate mass and LTQ XL ion trap massspectrometers, each operating in positive ion electrospray mode. Samplesof Form A of ponatinib HCl (ASI Batch 110020), dissolved inacetonitrile, were introduced into the mass spectrometers via infusionby a syringe pump. The accurate mass for ponatinib HCl was obtained onthe Exactive mass spectrometer using full scan mode. The mass observedin this infusion experiment is m/z 533.2269 (MH+) with the calculatedexact mass being 533.2271 (MH+) yielding a mass difference of 0.2 mmu (Δppm of −0.38) (FIG. 10 top). The fragmentation spectrum of ponatinib HClon the Exactive mass spectrometer is shown in FIG. 10, and contains theproduct ions from m/z of 533.2269 (the molecular ion of ponatinib HCl),as well as ions from any other co-eluted compounds.

FIG. 11 shows MS fragmentation data obtained on the LTQ XL ion trap massspectrometer. FIG. 11(A) shows the full scan MS of m/z 533, (MH⁺) of thesample during infusion. FIG. 11(B) (MS² scan) shows the fragmentspectrum of the selected mass m/z 533. FIG. 11(C) and FIG. 11(D) showthe product ions from m/z 433 and 260 respectively; ions m/z 433, and260 were themselves the initial product ions from m/z 533 (the molecularion).

Single-crystal X-Ray diffraction analysis was employed to determine thecrystal structure of the Form A of ponatinib hydrochloride. Singlecrystals of ponatinib HCl, in the anhydrate HCl-1 form were obtainedusing the vapor diffusion into liquid crystallization method usingponatinib HCl CGAM Batch F08-06057. A single crystal obtained usingmethanol as a solvent with ethyl acetate as anti-solvent was analyzed bysingle crystal X-ray diffraction. From prior experiments, it was knownthat crystals of this form diffracted well, leading to the solution ofthe structure of ponatinib HCl shown in FIG. 12, with crystallographicparameters summarized in Table 2. The terminal nitrogen of thepiperazine is the site of protonation in ponatinib HCl, consistent withthe previously described NMR analysis of ponatinib HCl. The chloridecounter-ion occurs in the crystal structure immediately adjacent to thesite of protonation. Based on this structure analysis, it was determinedthat Form A is an anhydrated form.

TABLE 2 Crystal Data and Structure Refinement for PonatinibHydrochloride Form A. Identification code S11022 Empirical formulaC₂₉H₂₈F₃N₆O⁺ Cl⁻ Fw 569.02 T [K] 296(2) λ [Å] 0.71073 Crystal systemMonoclinic Space group C 2/c Unit cell dimensions: a [Å] 35.883(9) b [Å]7.306(3) c [Å] 25.684(6) β [°] 122.923(9) V [Å³] 5652(3) Z 8 D_(c)[g/cm³] 1.337 μ [mm⁻¹] 0.189 F(000) 2368 Crystal size [mm³] 0.40 × 0.30× 0.20 θ range for data collection [°] 3.2-32.5 Reflections collected29574 Independent reflections 10117 [R_(int) = 0.0395] Completeness to θ= 32.5° [%] 98.8 Max. and min. transmission 0.9632 and 0.9283Data/restraints/parameters 10117/0/473 Goodness-of-fit on F² 1.070 FinalR indices [I > 2σ(I)] R1 = 0.0644, wR2 = 0.1501 R indices (all data) R1= 0.0957, wR2 = 0.1672

The attenuated total reflectance (ATR) FT-IR spectrum of Form A ofponatinib HCl, ASI Batch 110020, is shown in FIG. 13. Table 3 provides asummary of selected IR band assignment of ponatinib HCl based on theFT-IR shown in FIG. 13.

TABLE 3 Selected IR Band Assignment of Ponatinib HCl Region inAbsorption band Frequency (cm⁻¹) FIG. 13 C—H stretch (νCH3, νCH2) 2938.1(2870-2960) A N—H stretch 3242.1 A C≡C stretch 2220.0 B C═O stretch(Amide 1) 1669.8 C N—H bending (Amide 2) 1531.8 D C—N stretch 1314.9 FC—F stretch 1122.6 H aromatic C—H out-of-plane bending 857.3, 789.7 I

In the FT-IR, the functional group region extends from 4000 to 1300cm-1. In the region from 3300 to 2800 cm-1 (region A), there aremultiple overlapping, absorption bands arising from stretchingvibrations between hydrogen and some other atom, likely amide N—Hstretching, aromatic C—H stretching (from the imidazo-pyridazineheterocycle and phenyl groups) and aliphatic C—H stretching (in methyland methylene groups), all present in the structure of ponatinib HCl. Aweak band in the 2100-2260 cm-1 (region B) is due to triple C—C bondstretching. A medium intensity band due to amide C═O stretching(Amide 1) can be expected in 1640-1690 cm-1 range, likely the bandobserved at 1669.8 cm-1 (region C). Secondary amide N—H bending givesabsorption bands in the 1500-1560 cm-1 range (Amide 2), where two strongbands are observed (region D). Multiple weak to medium bands observed inthe 1300-1600 cm-1 range are due to (hetero)aromaticresonance-stabilized double C—C and double C—N bonds (ring stretchingvibrations), and C—H bending vibrations (from methyl and methylenegroups) (region E). Aromatic and aliphatic amine C—N stretching bandscan be expected in the 1250-1335 cm-1 range and in the 1250-1020 cm-1range, respectively, where multiple bands are observed, including aparticularly strong band at 1314.9 cm-1 (regions F, G). The fingerprintregion, 1300 to 910 cm-1, is complex with a strong, broad band at 1122.6cm-1 (region H), likely due to C—F stretching. The aromatic region, 910to 650 cm-1, absorption bands are primarily due to the out-of-planebending of hetero-aromatic ring C—H bonds indicating the hetero-aromaticnature of the compound (region I). These data in the FT-IR spectrumsupport the proposed structure of Form A of ponatinib hydrochloride.

Experiments to determine the purity of Form A were carried out. Withreference to FIG. 14, it was determined that the purity of Form A ofponatinib hydrochloride is 99.8160 (area percent).

Characteristics of Form B (HCl2):

Form HCl2 was obtained from a solubility assessment in TFE/water and itwas converted to form HCl2b one day after storage of the measuring plateat ambient conditions, as confirmed by the XRPD re-measurement of thespecific sample. HCl2 was also obtained in the experiments performed inPhase 2 described herein from aqueous solvent systems (water andMeOH/water) and it also converted to form HCl2b upon storage at ambientconditions (see overview in FIG. 2).

Form B was analyzed by X-ray powder diffraction (XRPD). FIG. 15 showsXRPD patterns of (from bottom to top): starting material (Form A), FormHCl2 (Form B) (QSA12.1, solvent: water) and Form HCl2b (Form C)(QSA12.2, remeasurement after few days at ambient conditions). In theXRPD pattern of Form B shown in FIG. 15, at least one or all of thefollowing peaks in degrees two theta (2θ) is shown: 3.1; 6.5; 12.4;13.8; 15.4; 16.2; 17.4; 18.0; 20.4; 23.2; 24.4; 26.1; and 26.9. Forreference, in the XRPD pattern of Form C shown in FIG. 15, at least oneor all of the following peaks in degrees two theta (2θ) is shown: 6.5;12.4; 13.8; 17.4; 18.0; 20.6; 22.0; 23.0; 25.5; 26.5; and 27.4. Incertain embodiments, Form B is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 13.8;15.4; 17.4; 18.0; 26.1; and 26.9. In these embodiments, the XRPD patternof Form B and C shows two peaks, three peaks, four peaks or five peaks.

Experiments to determine the purity of Form B were carried out. Withreference to FIG. 15, it was determined that the purity of Form B ofponatinib hydrochloride is 99.7535% (area percent).

Characteristics of Form C (HCl2b):

Form C is a hydrated form. Form HCl2b was initially obtained from thesolubility assessment experiments, either by conversion of Form B, overa number of days under ambient conditions or directly from TFE/watersolvent mixtures. Form C was also obtained in the Phase 2 experimentsfrom aqueous solvent systems (water and water/DMSO) (see overview inFIG. 2).

Form C was analyzed by X-ray powder diffraction (XRPD). FIG. 17 showsXRPD patterns of (from bottom to top): starting material (HCl1) and FormHCl2b (QSA21.1, solvent: water). In the XRPD pattern of Form C shown inFIG. 17, at least one or all of the following peaks in degrees two theta(2θ) is shown: 3.1; 6.5; 12.4; 13.8; 17.4; 18.0; 20.6; 22.0; 23.0; 25.5;26.5; 27.4; 28.4; and 29.0. In certain embodiments, Form C ischaracterized by a XRPD pattern comprising one or more of the followingpeaks two theta (2θ): 13.8; 17.4; 18.0; and 25.5. In certainembodiments, the XRPD pattern of Form C shows two peaks, three peaks,four peaks or five peaks.

With reference to FIG. 18, the melting point of Form C of ponatinib HClwas determined by differential scanning calorimetry (DSC). The sample ofwas analyzed in a pin-holed crucible in the temperature range of 25° C.to 300° C. at a heating rate of 10° C. per minute using dry N₂ gaspurge. Intense endothermic events occurred at T_(peak)=122.9° C.,T_(peak)=158.2° C. and T_(peak)=256.2° C.

FIG. 19 shows TGA and SDTGA thermograms of QSA21.1. FIG. 20 shows a TGMSthermogram of Form C from experiment QSA21.1. A mass loss of 4.3%(water) is observed in the temperature interval 40° C.-140° C. TheAPI:water ratio was assessed as 1:1.4.

Experiments to determine the purity of Form C were carried out. Withreference to FIG. 21, it was determined that the purity of Form C ofponatinib hydrochloride is 99.7850% (area percent).

Characteristics of Form D (HCl3-Class):

HCl3-class was mostly obtained from aromatic solvents, as can be seen inthe overview in FIG. 2, with the exception of the MeOH/acetonitrilemixture. Form D was successfully reproduced at the 120 mg scale usingcooling-evaporative crystallization in toluene.

Based on the thermal analyses, the sample representative of the Form Dwas assigned as a toluene solvated form (API:toluene 1:0.5). The formdesolvated at 199.5° C., recrystallized and a second melting wasobserved at 257.6° C. (most likely corresponding to the melting point ofForm A). HCl3-class is mildly hygroscopic, with 2.5% water mass uptakeat 95% RH. The process was reversible regarding to physical stabilityand sample appearance.

HCl3-class sample was found to be physically stable after 8 monthsstorage under ambient conditions and following the DVS cycle. However,HCl3-class sample converted to HCl1 after 1 week in the humidity chamber(40° C./75% RH).

Form D was analyzed by X-ray powder diffraction (XRPD). FIG. 22 showsXRPD patterns of a XRPD overlay of (from bottom to top): HCl1 (AP24534HCl salt starting material), HCl3-class (PSM17, solvent: toluene), HCl3(PSM1, solvent: toluene), HCl1+HCl3 (PSM1 after one week at 40° C./75%RH) and HCl3 (PSM1 after DVS). In the XRPD pattern shown in FIG. 22, atleast one or all of the following peaks in degrees two theta (2θ) isshown for HCl3: 8.2; 10.1; 10.9; 14.9; 16.0; 16.3; 16.8; 17.7; 18.7;20.2; 22.9; 24.0; 25.6; 26.7; and 28.5. In certain embodiments, Form Dis characterized by a XRPD pattern comprising one or more of thefollowing peaks two theta (2θ): 8.2; 10.1; 14.9; and 25.6. In the XRPDpattern shown in FIG. 22, at least one or all of the following peaks indegrees two theta (2θ) is shown for HCl3+HCl1: 6.5; 7.4; 12.5; 13.6;14.1; 16.7; 17.4 18.0; 19.3; 20.4 21.8; 24.0; 25.1; 26.3; and 28.0. Incertain embodiments, HCl3+HCl1 is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 12.5;19.3; and 26.3. In certain embodiments, the XRPD pattern of Form D showstwo peaks, three peaks, four peaks or five peaks.

With reference to FIG. 23, the melting point of Form D of ponatinib HCl(PSM1) was determined by differential scanning calorimetry (DSC). Thesample of was analyzed in a pin-holed crucible in the temperature rangeof 25° C. to 300° C. at a heating rate of 10° C. per minute using dry N₂gas purge. Intense endothermic events occurred at T_(peak)=199.5° C.,T_(peak)=204.1° C. and T_(peak)=257.6° C.

With reference to FIG. 24, TGA and SDTGA thermograms of Form D (PSM1)are provided. A mass loss of 7.7% (toluene, ratio API:Solvent is 1:0.51)was observed in the temperature interval 120° C.-220° C.

With reference to FIG. 25, a FT-IR spectrum of the region of 1750-500cm⁻¹ is shown. These data support the proposed structure of Form D ofponatinib hydrochloride. In addition, this spectrum show the uniqueidentity of Form D relative to Form A.

Experiments to determine the purity of Form D (PSM1) were carried out.With reference to FIG. 26, it was determined that the purity of Form Dof ponatinib hydrochloride is 97.3664% (area percent).

Characteristics of Form E (Mixture of HCl4+HCl1):

HCl4 was only obtained as a mixture with Form A from a grindingexperiment with hexafluorobenzene (see overview in FIG. 2).

Form E of ponatinib hydrochloride was found not to be physically stableupon storage at ambient conditions. The mixture HCl1+HCl4 wasre-measured by XRPD after 8 months of storage and it had converted toForm A.

Characteristics of Form F (HCl5-Class):

Form HCl5 was obtained from one vapor diffusion onto solids experimentdescribed here in butyl acetate (see overview in FIG. 2). HCl5-class wascharacterized by DSC, cycling-DSC, TGMS, FTIR, HPLC and DVS. Thephysical stability under short-term storage conditions (i.e. one week at40° C. and 75% RH) was investigated. HCl5-class samples were physicallystable, as assessed by XRPD, after 8 months storage under ambientconditions. After 1 week in the humidity chamber (40° C./75% RH), thematerial was still HCl5-class, however with a slightly different XRPDpattern.

A DVS experiment showed that HCl5-class is highly hygroscopic, with a37% water mass adsorption. The material lost its crystallinity asindicated by the XRPD following the DVS experiment.

Form F was successfully scaled up at the 120 mg scale using the sameconditions as those of the original experiment to identify thepreviously discovered polymorphs. Two scale-up experiments wereperformed and the corresponding XRPD patterns indicated formsisostructural to HCl5. These isostructural forms together with HCl5 andHCl5b were designated HCl5-class or Form F.

FIG. 27 shows XRPD patterns of a XRPD overlay of (from bottom to top):HCl1 (Form A starting material); HCl5 and HCl5b (VDS28 wet and dry,solvent: butyl acetate); HCl5-class (VDS1, solvent: butyl acetate), Lowcrystalline (VDS1 after DVS); HCl5-class (VDS2, solvent: butyl acetate);and HCl5-class (VDS2 after one week at 40°, 75% RH). In the XRPD patternshown in FIG. 27, at least one or all of the following peaks in degreestwo theta (2θ) is shown for HCl5: 6.8; 9.8; 12.4; 16.2; 17.9; 19.0;24.0; and 25.1. In certain embodiments, HCl5 is characterized by a XRPDpattern comprising one or more of the following peaks two theta (2θ):9.8; 12.4; and 25.1. In the XRPD pattern shown in FIG. 27, at least oneor all of the following peaks in degrees two theta (2θ) is shown forHCl5-class (top pattern): 7.9; 8.7; 9.7; 11.4; 15.6; 16.5; and 25.8. Incertain embodiments, HCl5-class is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 15.6;16.5; 25.8. In certain embodiments, the XRPD pattern of Form F shows twopeaks, three peaks, four peaks or five peaks.

With reference to FIG. 28, the melting point of Form F of ponatinib HCl(PSM1) was determined by differential scanning calorimetry (DSC).Samples from two different experiments were analyzed in a pin-holedcrucible in the temperature range of 25° C. to 300° C. at a heating rateof 10° C. per minute using dry N₂ gas purge. A sample from oneexperiment (VDS1, top curve) evidenced intense endothermic eventsoccurred at T_(peak)=120.7° C., T_(peak)=184.3° C. and T_(peak)=209.4°C. A sample from another experiment (VDS2, bottom curve) evidencedintense endothermic events occurred at T_(peak)=122.1° C.,T_(peak)=209.7° C. and T_(peak)=252.1° C.

A cycling DSC experiment showed that upon desolvation, HCl5-classconverted to a form designated “HCl5-desolvate”, which melted at circa210° C.

With reference to FIG. 29, a TGA/SDTA thermogram of Form F (VDS1, top)and TGMS (bottom) thermogram are provided. A mass loss of 17.1% (Butylacetate, ratio API:Solvent 1:1.01) was observed in the temperatureinterval 25° C.-160° C. TG-MS analyses showed that HCl5-class is a butylacetate solvate with a ratio API:butyl acetate of 1:1 and it desolvatesat around 120° C. FIG. 30 provides a corresponding TGA/SDTA (top) andTGMS (bottom) thermogram of Form F for VDS2. A mass loss of 16.6% (Butylacetate, ratio API:Solvent 1:0.98) was observed in the temperatureinterval 25° C.-160° C.

With reference to FIGS. 31 and 32, a FT-IR spectrum of the region of1750-500 cm⁻¹ is shown. These data support the proposed structure ofForm F of ponatinib hydrochloride. In addition, these spectra show theunique identity of Form F relative to Form A.

Experiments to determine the purity of Form F (VDS2) were carried out.With reference to FIG. 33, it was determined that the purity of Form Dof ponatinib hydrochloride is 98.2833% (area percent).

Characteristics of Form G (HCl5b):

Form G of ponatinib hydrochloride was obtained by conversion of HCl5,upon drying for 3 days under full vacuum. HCl5b form was found to bephysically stable after 8 months storage under ambient conditions.

Characterization data for Form G is provided herein in the context ofForm F.

Characteristics of Form H (HCl6-Class):

HCl6 was obtained from two experiments; vapor into solution and vaporonto solids, in MeOH/water and MeOH solvent systems, respectively (seeoverview in FIG. 2). Different time points of material sampling showedthat the corresponding XRPD patterns were slightly different, withoutbeing bound by theory, indicating that HCl6 is a class of forms, likelyisostructural. HCl6-class was successfully scaled up to 120 mg using thesame conditions as those of the MeOH vapor onto solids experiment of theoriginal screening experiment.

HCl6-class was characterized by DSC, cycling-DSC, TGMS, FTIR, HPLC andDVS. The physical stability under short-term storage conditions (i.e.one week at 40° C. and 75% RH) was investigated. Form H samples werephysically stable, as assessed by XRPD, after 8 months storage underambient conditions. After 1 week in the humidity chamber (40° C./75%RH), the material was still HCl6-class, however with a slightlydifferent XRPD.

FIG. 34 shows XRPD patterns of a XRPD overlay of (from bottom to top):Form A (ponatinib hydrochloride starting material), HCl6-class (VDS6,solvent: methanol), HCl6-class (VDS3, solvent: methanol), HCl6 (VDS3after DVS), HCl6-class (VDS3 after climate chamber), HCl6-class (VDS4,solvent: methanol) and HCl6-class (VDS4 after DVS). In the XRPD patternshown in FIG. 34, at least one or all of the following peaks in degreestwo theta (2θ) is shown for HCl6 (immediately above Form A pattern):5.9; 8.1; 9.5; 10.7; 13.4; 16.0; 17.0; 22.0; 22.8; 24.7; and 28.3. Incertain embodiments, HCl6 is characterized by a XRPD pattern comprisingone or more of the following peaks two theta (2θ): 8.1; 10.7; 13.4;24.7; and 28.3. In the XRPD pattern shown in FIG. 34, at least one orall of the following peaks in degrees two theta (2θ) is shown forHCl6-class (top pattern): 8.0; 10.2; 10.9; 11.8; 14.1; 15.4; 16.3; 19.9;22.3; 23.7; 25.0; and 28.2. In certain embodiments, HCl6-class ischaracterized by a XRPD pattern comprising one or more of the followingpeaks two theta (2θ): 10.2; 15.4; 23.7; 25.0. In certain embodiments,the XRPD pattern of Form F shows two peaks, three peaks, four peaks orfive peaks. Although XRPD analysis of both samples showed that similarpatterns were observed after the DVS run, the TGMS analysis of VDS4showed that methanol molecules were no longer present in the sample butthey had been replaced by water molecules (forming presumably ahemi-hydrated form belonging to the HCl6-class.

With reference to FIG. 35, the melting point of Form H of ponatinib HClwas determined by differential scanning calorimetry (DSC). Samples fromtwo different experiments were analyzed in a pin-holed crucible in thetemperature range of 25° C. to 300° C. at a heating rate of 10° C. perminute using dry N₂ gas purge. A sample from one experiment (VDS3, topcurve) evidenced an intense endothermic event at T_(peak)=219.4° C. Asample from another experiment (VDS4, bottom curve) evidenced intenseendothermic events occurred at T_(peak)=219.4° C. and T_(peak)=256.8° C.

With reference to FIG. 36, a TGA/SDTA thermogram of Form H (VDS3, top)and TGMS (VDS3, bottom) thermogram are provided. A mass loss of 5.4%(Methanol, ratio API:Solvent 1:1.01) was observed in the temperatureinterval 30° C.-150° C. and a mass loss of 0.3% (Methanol ratioAPI:Solvent 1:0.05) was observed in the temperature interval 190°C.-220° C. A corresponding TGA/SDTA thermogram of Form H (top) and TGMS(bottom) thermogram is shown at FIG. 37 for VDS4. A mass loss of 3.3%(Methanol, ratio API:Solvent 1:0.6) was observed in the temperatureinterval 30° C.-150° C. and a mass loss of 0.7% (Methanol, ratioAPI:Solvent 1:0.12) was observed in the temperature interval 190°C.-220° C.

With reference to FIGS. 38 and 39, a FT-IR spectrum of the region of1750-500 cm⁻¹ is shown. These data support the proposed structure ofForm H of ponatinib hydrochloride. In addition, these spectra show theunique identity of Form H relative to Form A.

Experiments to determine the purity of Form H (VDS4) were carried out.With reference to FIG. 40, it was determined that the purity of Form Hof ponatinib hydrochloride is 97.9794% (area percent).

Characteristics of Form I (HCl6 Desolvate):

A cycling DSC experiment conducted in connection with the experimentsfor Form H showed that upon desolvation, HCl6-class converted to a formdesignated “HCl6-desolvate”, which melted at circa 220° C.

Characteristics of Form J (HCl7):

Form J is a pentahydrate of ponatinib HCl and was discovered in thecontext of a single crystal analysis. Form J is the most stable hydratedstructure identified, as competitive slurries in water between thetrihydrate and pentahydrate showed.

Single crystals of suitable size were obtained in the vapor diffusionexperiment performed with the solvent mixture methanol/water 20:80 andn-butyl acetate as anti-solvent. One parallelepiped single crystal ofapproximate size 0.45×0.25×0.12 mm was collected from thecrystallization vial and mounted on a glass fiber. The crystallographicdata (collected up to θ=27.5°) are listed in Table 4.

TABLE 4 Crystal Data and Structure Refinement for Form J Identificationcode Form J (Pentahydrate) Empirical formula C₂₉H₂₈F₃N₆O⁺•Cl⁻•5 H₂O Fw659.10 T [K] 296(2) λ [Å] 0.71073 Crystal system Monoclinic Space groupP 2₁/c Unit cell dimensions a [Å] 16.7220(4) b [Å] 7.5920(2) c [Å]29.920(8) β [°] 121.543(9) V [Å³] 3237.2(9) Z 4 D_(c) [g/cm³] 1.352 μ[mm⁻¹] 0.186 F(000) 1384 Crystal size [mm] 0.45 × 0.25 × 0.12 θ rangefor data collection [°] 2.8 → 27.5 Reflections collected 24343Independent reflections 7410 [R_(int) = 0.0450] Completeness to θ =27.5° [%] 99.6 Max. and min. transmission 0.9781 and 0.9211Data/restraints/parameters 7410/0/542 Goodness-of-fit on F² 1.030 FinalR indices [I > 2σ(I)] R1 = 0.0630, wR2 = 0.1502 R indices (all data) R1= 0.1064, wR2 = 0.1758

The asymmetric unit comprises the cation, the chloride anion and fivewater molecules (pentahydrate). The water molecules are connected viahydrogen bonding (H-Bonds) with the anion, the cation and neighboringwater molecules.

The important consequence of the present H-Bonds arrangement is the factthat in this crystal both charged atoms (i.e. the protonated nitrogenfrom the API and the chloride anion) are bridged/separated by severalmolecules of water.

FIG. 43 shows a characteristic X-Ray Powder Diffraction (XRPD) patternfor Form J of ponatinib hydrochloride. The XRPD pattern of Form J shownin FIG. 43 shows at least one or more of the peaks having a relativeintensity of 20% or greater in degrees two theta (2θ): 6.1; 7.0; 13.3;16.4; 20.7; 22.2; 23.9; 25.5; and 29.1. In certain embodiments, Form Jis characterized by a XRPD pattern comprising one or more of thefollowing peaks two theta (2θ): 7.0; 22.2; and 25.5. In certainembodiments, the XRPD pattern of Form J shows two peaks, three peaks,four peaks or five peaks.

Characteristics of Form K (HCl8):

Form K was discovered in the context of a single crystal analysis. Thesingle crystals were grown in the slow evaporation experiment conductedwith TFE/H2O mixture 50:50. One block-like single crystal of approximatesize 0.40×0.30×0.25 mm was analyzed. Although the crystal was large, itdiffracted quite poorly, which is an indication of partial disorder inthe structure. Therefore the measurement was recorded only up to θ=25°.The crystallographic parameters are listed in Table 5.

TABLE 5 Crystal data and structure refinement for Form K Identificationcode Form K (Trifluorethanol solvate hydrate) Empirical formulaC₂₉H₂₈F₃N₆O⁺•Cl⁻•C₂H₃F₃O•0.75 H₂O Fw 682.58 T [K] 296(2) λ [Å] 0.71073Crystal system Triclinic Space group P-1 Unit cell dimensions a [Å]9.726(2) b [Å] 12.270(3) c [Å] 14.476(4) α [°] 91.694(7) β [°] 98.963(8)γ [°] 99.390(9) V [Å³] 1680.9(7) Z 2 D_(c) [g/cm³] 1.349 μ [mm⁻¹] 0.187F(000) 707 Crystal size [mm³] 0.40 × 0.30 × 0.25 θ range for datacollection [°] 2.1 → 25 Reflections collected 8812 Independentreflections 5866 [R_(int) = 0.0247] Completeness to θ = 25° [%] 99.0Max. and min. transmission 0.9548 and 0.9290 Data/restraints/parameters5866/0/440 Goodness-of-fit on F² 1.035 Final R indices [I > 2σ(I)] R1 =0.0762, wR2 = 0.2160 R indices (all data) R1 = 0.0931, wR2 = 0.2366

The structure of the mixed TFE solvated/hydrated form comprises thecation, the chloride anion and two neutral entities: thetrifluoroethanol and the water molecules. In this structure, althoughwater molecules are involved in the H-bonding they do not separate thecharged atoms (contrary to the pentahydrated and trihydrated forms. TheTFE and water molecules acted only as donors in the hydrogen bondingnetwork. In particular for the water molecules, only one of the hydrogenatoms acts as donor, which could be responsible for the disorder of thewater molecules and the fact that the ratio of the water moleculescompared to the API molecules is not stoichiometric.

FIG. 44 shows a characteristic X-Ray Powder Diffraction (XRPD) patternfor Form K of ponatinib hydrochloride. The XRPD pattern of Form K shownin FIG. 44 shows at least one or more of the peaks having a relativeintensity of 20% or greater in degrees two theta (2θ): 6.1; 7.4; 13.5;17.4; 18.5; 20.7; 23.9; and 28.3. In certain embodiments, Form K ischaracterized by a XRPD pattern comprising one or more of the followingpeaks two theta (2θ): 7.4 and 23.9. In certain embodiments, the XRPDpattern of Form K shows two peaks, three peaks, four peaks or fivepeaks.

Characteristics of Amorphous Form of Ponatinib Hydrochloride:

FIG. 45 shows XRPD patterns of Form A of ponatinib hydrochloride (bottompattern) and amorphous ponatinib hydrochloride (top pattern) (solvent:2,2,2-trifluroethanol). It is readily apparent that Form A has adistinct set of peaks at particular angles two theta whereas theamorphous ponatinib hydrochloride does not have any defined peaks.

In addition, amorphous ponatinib hydrochloride has a unique meltingtemperature as compared to Form A of amorphous ponatinib hydrochloride.FIG. 46 shows a characteristic Differential Scanning calorimetry (DSC)thermogram of amorphous ponatinib hydrochloride. An intense endothermicevent with a peak of 259.4° C. was observed, corresponding to themelting point of the amorphous form. This melting point is distinct fromthat observed with Form A of ponatinib hydrochloride, which demonstrateda melting point of 264.1° C.

Unique and distinct physical properties of amorphous ponatinibhydrochloride and Form A of ponatinib hydrochloride do not seem to beattributed to purity of the respective materials. In the case ofamorphous ponatinib hydrochloride, the material was determined by HPLCto have a purity of 99.7877% (area percent) (see FIG. 47), whereas thepurity of Form A of ponatinib hydrochloride was determined to be 99.8%(area percent).

Example 1 Discovery of Polymorphic Forms

Initial efforts to discover polymorphic forms of ponatinib hydrochloridewere divided into two phases. Phase 1 included starting-materialcharacterization, feasibility testing and solubility studies to providedata for the solvent selection for Phase 2. Phase 2 included 192polymorph screening experiments at milliliter (ml) scale. These initialefforts led to the discovery of eight polymorphic forms, Form A, Form B,Form C, Form D, Form E, Form F, Form G and Form H.

Phase 1: Starting Material Characterization

Approximately 24 grams of the compound ponatinib hydrochloride wasprovided as a light yellow solid. This starting material wascharacterized by XRPD, digital imaging, DSC, TGMS and HPLC. The startingmaterial,3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemono hydrochloride, is provided as a crystalline material (designatedHCl1) and its chemical purity was assessed by HPLC as 99.8%. TGA andTGMS analyses showed 0.7% of mass loss (residual ethanol) in thetemperature interval 25° C.-240° C. prior to the thermal decompositionprocess. DSC analysis showed an endothermic event with T_(peak)=264.8°C., probably related to melting and/or decomposition of the compound,3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemono hydrochloride.

Phase 1: Solubility Study

Quantitative solubility testing was performed on ponatinib hydrochloridestarting material, employing a set of 20 solvents. Slurries wereprepared with an equilibration time of 24 hours after which the slurrieswere filtrated. The solubility was determined from the saturatedsolutions by HPLC. The residual solids were characterized by XRPD. Theresults are summarized in Table 6.

TABLE 6 Solubility Study of 3-(imidazo[1,2-b]pyridazin-3-ylethynl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide mono hydrochloride Solubility XRPDExperiment Solvent name (mg/ml) Form¹ QSA1 Diethylene glycoldiethylether 0.36 HCl1 QSA2 Diethyl ether UR, <0.22² HCl1 QSA3 DimethylSulfoxide 71.65  HCl1 QSA4 Isobutyl isobutyrate UR, <0.22² HCl1 QSA5Dimethylacetamide N,N- 35.64  HCl1 QSA6 Pentyl ether UR, <0.22² HCl1QSA7 Cyclohexanone 0.64 HCl1 QSA8 Xylene, p- UR, <0.22² HCl1 QSA9Isobutanol 0.91 HCl1 QSA10 Butyl acetate UR, <0.22² HCl1 QSA11 Heptane,n- UR, <0.22² HCl1 QSA12 Water 1.67 HCl2 QSA13 Trifluoroethanol 2,2,2-OR³ Am⁴ QSA14 Hexafluorobenzene UR, <0.22² HCl1 QSA15 Isopropanol 0.64HCl1 QSA16 Isopropyl acetate UR, <0.22² HCl1 QSA17 Dichloroethane 1,2-0.27 HCl1 QSA18 Acetonitrile 0.44 HCl1 QSA19 Tetrahydrofuran 0.42 HCl1QSA20 Methanol 29.66  HCl1 QSA21 Water 1.85 HCl2b QSA23 Heptane, n- UR,<0.22² HCl1 QSA24 Heptane, n- UR, <0.22² HCl1 QSA25 Acetonitrile 0.38HCl1 QSA26 Acetonitrile 0.39 HCl1 QSA27 Dimethyl sulfoxide 86.44  HCl1QSA28 Dimethyl sulfoxide 85.18  HCl1 QSA29 Diethyl ether UR, <0.22² HCl1QSA30 Water 1.66 HCl2b QSA31 Dimethyl sulfoxide 93.14  HCl1 QSA322-Methyltetrahydrofuran UR, <0.22² HCl1 QSA33 Ethanol 4.58 HCl1 Alltests were conducted at room temperature with stirring. ¹The solid formobtained from the slurry was assessed based on the XRPD analysis. ²UnderRange, lower then detection limit, the concentration is lower than 0.22mg/ml ³Over Range, the material was dissolved, the concentration ishigher then 200 mg/ml. ⁴Amorphous

In 19 of the experiments shown in Table 6, the materials analyzedfollowing the solubility assessments in 19 different solvents appearedto be the same form as the starting material designated form HCl1. Inthe experiment QSA13 performed in 2,2,2-trifluoroethanol, the materialdissolved completely at the selected concentration and the sampleobtained after evaporation of the solvent resulted in amorphousmaterial. The solids from two slurries in water (QSA12 and QSA21)resulted in two different forms, Form HCl2 and Form HCl2b, respectively.After a few days stored at ambient conditions, the form HCl2 convertedto Form HCl2b and it could therefore not be further characterized. Uponfurther characterization, the Form HCl2b was determined to be a hydratedform (ratio API/water 1:1.4).

Phase 1: Feasibility Study

Feasibility tests were performed to attempt to obtain amorphous startingmaterial that could be employed in some crystallization techniques ofthe Phase 2 portion of the study. Two techniques were employed i.e.grinding and freeze-drying. The results are presented below.

Grinding. Two grinding experiments were performed with two differentdurations at a frequency of 30 Hz. After 60 minutes of grinding, thecrystalline starting material converted to amorphous. After 120 min, theresulting material remained amorphous with a chemical purity of 99.6%.

Freeze-drying. Eight freeze-drying experiments were performed with3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemono hydrochloride. These experiments are summarized in Table 7.

TABLE 7 Freeze-drying feasibility study of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide mono hydrochloride Solvent Exper- Formcontent Purity iment Solvent (XRPD) (%)¹ (%)² GEN2 Dimethyl sulfoxide —(not dry) — — GEN3 Methanol Am powdery  0.9 99.8 GEN42,2,2-Trifluoroethanol/ Am powdery 10.8 — Water 90/10 GEN52,2,2-Trifluoroethanol/ Am powdery  1.5 99.8 Water 50/50 GEN62,2,2-Trifluoroethanol Am powdery 11.0 — GEN7 Tetrahydrofuran — — — GEN82-Methyltetrahydrofuran — — — GEN9 Dichloromethane — — — ¹Based on theTGMS results. ²Chemical purity determined by HPLC.

The solubility of compound ponatinib hydrochloride in tetrahydrofuran,2-methyltetrahydrofuran and dichloromethane was too low to apply thefreeze drying procedure in good conditions. With solvents such asmethanol, 2,2,2-trifluoroethanol (TFE) and TFE/water mixtures, amorphousmaterial was obtained. In the samples obtained from neat TFE or withhigh TFE content in the solvent mixtures, 11% of residual solvent wasdetected in the dried powders (according to the TGMS results). Thesamples obtained from methanol and TFE/water 50:50 contained lessresidual solvent only 0.9% and 1.5%, respectively. The amount ofresidual solvent in the amorphous material produced from TFE/water 50:50could be reduced to below 1% after extra drying for 24 hours. For bothamorphous samples obtained from methanol and TFE/water 50:50, thechemical purity was assessed to be 99.8% by HPLC. Because creeping wasobserved in the freeze-drying experiment with methanol, the procedureusing TFE/water 50:50 was selected to be used to produce the amorphousponatinib hydrochloride to be used in the cooling-evaporationcrystallizations and vapor diffusion onto solids experiments of Phase 2.

Phase 2: Polymorph Discovery

The polymorph screening experiments for ponatinib hydrochloride werecarried out at milliliter (ml) scale using 192 different conditions inwhich six different crystallization procedures were applied: (1)cooling-evaporation; (2) anti-solvent addition; (3) grinding; (4)slurry; (5) vapor diffusion into solutions; and (6) vapor diffusion ontosolids. After the screening experiments were completed, the materialswere collected and analyzed by XRPD and digital imaging.

Cooling-Evaporative Crystallization Experiments. The 36cooling-evaporative experiments shown at Table 8 at ml scale wereperformed in 1.8 ml vials, employing 36 different solvents and solventmixtures and 1 concentration. In each vial, 25 mg of amorphous ponatinibhydrochloride was weighed. Then the screening solvent was added to reacha concentration of circa 60 mg/ml. The vials, also containing a magneticstirring bar, were closed and placed in an Avantium Crystal 16 toundergo a temperature profile, (as described in Table 9 below). Themixtures were cooled to 5° C. and held at that temperature for 48 hoursbefore placing the vials under vacuum. The solvents were evaporated forseveral days at 200 mbar or 10 mbar and analyzed by XRPD and digitalimaging.

TABLE 8 Experimental conditions for the 36 ml experiments using thecooling-evaporation method Exper- Weight Volume iment Solvent (mg) (μl)PSM1 Methyl butyl ether, tert- 24.8 400 PSM2 Methyl acetate 24.0 400PSM3 Chloroform 25.1 400 PSM4 Methanol 24.1 400 PSM5 Tetrahydrofuran21.9 400 PSM6 Hexane, n- 21.8 400 PSM7 Ethanol 25.2 400 PSM8 Cyclohexane23.3 400 PSM9 Acetonitrile 21.8 400 PSM10 Ethylene glycol dimethyl ether23.1 400 PSM11 Isopropyl acetate 20.8 400 PSM12 Heptane, n- 25.0 400PSM13 Water 23.3 400 PSM14 Methylcyclohexane 25.2 400 PSM15 Dioxane,1,4- 27.2 400 PSM16 Isobutanol 21.9 400 PSM17 Toluene 23.3 400 PSM18Butyl acetate 23.1 400 PSM19 Hexanone, 2- 24.4 400 PSM20 Chlorobenzene21.5 400 PSM21 Ethoxyethanol, 2- 22.9 400 PSM22 Xylene, m- 22.6 400PSM23 Cumene 23.4 400 PSM24 Anisole 22.0 400 PSM25 Methanol/Chloroform(50/50) 23.9 400 PSM26 Methanol/Ethyl formate (50/50) 24.8 400 PSM27Methanol/Acetonitrile (50/50) 23.2 400 PSM28 Acetonitrile/Chloroform(50/50) 23.2 400 PSM29 Cyclohexane/Tetrahydrofuran 22.9 400 (50/50)PSM30 Cyclohexane/Chloroform (50/50) 23.8 400 PSM31 Cyclohexane/Dioxane,1,4- (50/50) 24.9 400 PSM32 Cyclohexane/N-methyl-2- 22.1 400 pyrrolidone(50/50) PSM33 Heptane, n-/Cyclohexane (50/50) 23.9 400 PSM34Tetrahydrofuran/N-methyl-2- 24.9 400 pyrrolidone (50/50) PSM35Tetrahydronaphthalene, 1,2,3,4-/ 22.9 400 Cyclohexane (50/50) PSM36Tetrahydronaphthalene, 1,2,3,4-/ 22.6 400 Cumene (50/50)

TABLE 9 Temperature profile employed for the 36 cooling-evaporativeexperiments Experiments Heating rate T_(initial) Hold Cooling rateT_(final) Hold PSM1-36 10 60 60 1 5 48

Crash-crystallization with anti-solvent addition Experiments. For thecrash-crystallization experiments, 36 different crystallizationconditions were applied, using 1 solvent and 24 different anti-solvents(see Table 9). The anti-solvent addition experiments have been performedforwards. A stock solution was prepared, the concentration of ponatinibhydrochloride being that attained at saturation at ambient temperatureafter equilibration for 24 hours before filtering into 8 ml vials. Toeach of these vials a different anti-solvent was added, using a solventto anti-solvent ratio of 1:0.25. Because no precipitation occurred, thisratio was increased to 1:4 with a waiting time of 60 minutes betweeneach addition. As no precipitation occurred yet, the solvents werecompletely evaporated under vacuum at room temperature. Afterevaporation, the experiments resulted to have no yield.

TABLE 9 crash-crystallization experiments Ratio Exper- S:AS imentSolvent Anti-Solvent (1:x) AS1 Ethyl formate Methyl butyl ether, tert- 4AS2 Ethyl formate Chloroform 4 AS3 Ethyl formate Diisopropyl ether 4 AS4Ethyl formate Cyclohexane 4 AS5 Ethyl formate Trimethylpentane, 2,2,4- 4AS6 Ethyl formate Heptane, n- 4 AS7 Ethyl formate Octane, n- 4 AS8 Ethylformate Nonane, n- 4 AS9 Ethyl formate Diethoxymethane 4 AS10 Ethylformate Dimethyl-4-heptanone, 2,6- 4 AS11 Ethyl formateMethyltetrahydrofuran, 2- 4 AS12 Ethyl formate Cumene 4 AS13 Ethylformate Methylcyclohexane 4 AS14 Ethyl formate Acetonitrile 4 AS15 Ethylformate Fluorobenzene 4 AS16 Ethyl formate Diethyl carbonate 4 AS17Ethyl formate Dimethyl-3-butanone, 2,2- 4 AS18 Ethyl formateDichloroethane, 1,2- 4 AS19 Ethyl formate Xylene, p- 4 AS20 Ethylformate Isoamyl acetate 4 AS21 Ethyl formate Toluene 4 AS22 Ethylformate Cyclohexanone 4 AS23 Ethyl formate Chlorobenzene 4 AS24 Ethylformate Anisole 4 AS25 Dimethyl Sulfoxide Water 4 AS26 DimethylSulfoxide Tetrahydrofuran 4 AS27 Dimethyl SulfoxideMethyltetrahydrofuran, 2- 4 AS28 Dimethyl Sulfoxide Acetonitrile 4 AS29Dimethylacetamide N,N- Water 4 AS30 Dimethylacetamide N,N-Tetrahydrofuran 4 AS31 Dimethylacetamide N,N- Methyltetrahydrofuran, 2-4 AS32 Dimethylacetamide N,N- Acetonitrile 4 AS33 Methanol Water 4 AS34Methanol Tetrahydrofuran 4 AS35 Methanol Methyltetrahydrofuran, 2- 4AS36 Methanol Acetonitrile 4

Grinding Experiments. The drop-grinding technique uses a small amount ofsolvent added to the material3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemono hydrochloride, which is grinded in a stainless steel grinder jarwith 2 stainless steel grinding balls. In this manner, the effect of 24different solvents (see Table 10) was investigated. Typically 30 mg ofstarting material was weighed in the grinding container and 10 μl ofsolvent was added to the container. The grinding experiments wereperformed at 30 Hz during 120 min. Each wet material was subsequentlyanalyzed by XRPD and digital imaging.

TABLE 10 Experimental Conditions for Grinding Experiments Exper- WeightVolume iment Solvent (mg) (μl) GRP1 Hexafluorobenzene 30.6 10 GRP2Cyclohexane 31.4 10 GRP3 Acetonitrile 28.8 10 GRP4 Ethylene glycoldimethyl 28.6 10 ether GRP5 Diethoxymethane 29.9 10 GRP6 Heptane, n-31.0 10 GRP7 Trimethylpentane, 2,2,4- 31.0 10 GRP8 Water 30.0 10 GRP9Nitromethane 30.0 10 GRP10 Dioxane, 1,4- 29.8 10 GRP11 Trifluorotoluene,alpha, 30.5 10 alpha, alpha- GRP12 Toluene 30.4 10 GRP13 Nitropropane,2- 30.3 10 GRP14 Nitropropane, 1- 30.4 10 GRP15 Xylene, p- 30.6 10 GRP16Fluorooctane, 1- 30.6 10 GRP17 Isoamyl acetate 30.3 10 GRP18 Xylene o-29.0 10 GRP19 Nonane, n- 29.8 10 GRP20 Cyclohexanone 29.8 10 GRP21Diethyleneglycol- 29.7 10 dimethylether GRP22 Butylbenzene, sec- 29.1 10GRP23 Decane 28.9 10 GRP24 Limonene, (R)-(+)- 28.6 10

Slurry Experiments. A total of 48 slurry experiments were performed withthe compound ponatinib hydrochloride and 24 solvents at 10° C. and 30°C., for 2 weeks. Table 11 summarizes the experimental conditions. Theexperiments were carried out by stirring a suspension of the material ina solvent at a controlled temperature. At the end of the slurry time,the vials were centrifuged and solids and mother liquids separated. Thesolids were further dried under full vacuum at room temperature andanalyzed by XRPD and digital imaging.

TABLE 11 Experimental Conditions for the Slurry Experiments Temper-Weight Volume ature Experiment Solvent (mg) (ul) (° C.) SLP1 Methylbutyl ether, tert- 26.4 250 10 SLP2 Methyl acetate 28.9 250 10 SLP3Chloroform 25.0 250 10 SLP4 Methanol 23.0 250 10 SLP5 Tetrahydrofuran25.9 250 10 SLP6 Hexane, n- 23.8 250 10 SLP7 Ethanol 24.1 250 10 SLP8Cyclohexane 27.0 250 10 SLP9 Acetonitrile 28.5 250 10 SLP10Dimethoxyethane, 1,2- 26.6 200 10 SLP11 Isopropyl acetate 24.1 250 10SLP12 Heptane, n- 25.3 250 10 SLP13 Water 22.6 250 10 SLP14Methylcyclohexane 24.6 250 10 SLP15 Dioxane, 1,4- 26.7 250 10 SLP16Isobutanol 25.1 250 10 SLP17 Toluene 24.0 250 10 SLP18 Butyl acetate26.7 250 10 SLP19 Hexanone 2- 25.0 250 10 SLP20 Chlorobenzene 26.0 25010 SLP21 Ethoxyethanol, 2- 26.0 250 10 SLP22 Xylene, m- 25.8 250 10SLP23 Cumene 24.5 250 10 SLP24 Anisole 26.7 250 10 SLP25 Methyl butylether, tert- 23.7 250 30 SLP26 Methyl acetate 28.2 250 30 SLP27Chloroform 26.6 250 30 SLP28 Methanol 25.5 250 30 SLP29 Tetrahydrofuran25.2 250 30 SLP30 Hexane, n- 27.1 250 30 SLP31 Ethanol 28.6 250 30 SLP32Cyclohexane 25.9 250 30 SLP33 Acetonitrile 28.4 250 30 SLP34Dimethoxyethane, 1,2- 23.2 200 30 SLP35 Isopropyl acetate 26.2 250 30SLP36 Heptane, n- 24.4 250 30 SLP37 Water 25.8 250 30 SLP38Methylcyclohexane 28.4 250 30 SLP39 Dioxane, 1,4- 26.7 250 30 SLP40Isobutanol 25.1 250 30 SLP41 Toluene 24.3 250 30 SLP42 Butyl acetate26.4 250 30 SLP43 Hexanone, 2- 26.1 250 30 SLP44 Chlorobenzene 25.2 25030 SLP45 Ethoxyethanol, 2- 25.4 250 30 SLP46 Xylene, m- 24.9 250 30SLP47 Cumene 24.5 250 30 SLP48 Anisole 25.3 250 30

Vapor Diffusion Into Solutions. For the vapour diffusion experiments,saturated solutions of ponatinib hydrochloride were exposed to solventvapours at room temperature for two weeks. A volume of saturatedsolution was transferred to an 8 ml vial which was left open and placedin a closed 40 ml vial with 2 ml of anti-solvent (see Table 12). Aftertwo weeks, the samples were checked for solid formation. The sampleswere dried under vacuum (200 mbar or 10 mbar) and resulted to have noyield. Based on the results, additional experiments were performed with12 different crystallization conditions as described in the table,experiments ID VDL25-VDL36.

TABLE 12 Experimental Conditions for the Vapor Diffusion Into SolutionsVolume Exper- solution iment Solvent of solution (ul) Anti-Solvent VDL1Ethyl formate 875 Pentane VDL2 Ethyl formate 875 Dichloromethane VDL3Ethyl formate 875 Methyl butyl ether, tert- VDL4 Ethyl formate 875Chloroform VDL5 Ethyl formate 875 Diisopropyl ether VDL6 Ethyl formate875 Cyclohexane VDL7 Ethyl formate 875 Trimethylpentane, 2,2,4- VDL8Ethyl formate 875 Heptane, n- VDL9 Ethyl formate 875 Octane, n- VDL10Ethyl formate 875 Diethoxymethane VDL11 Ethyl formate 875Methyltetrahydrofuran, 2- VDL12 Ethyl formate 875 MethylcyclohexaneVDL13 Ethyl formate 875 Acetonitrile VDL14 Ethyl formate 875Fluorobenzene VDL15 Ethyl formate 875 Diethyl carbonate VDL16 Ethylformate 875 Dimethyl-3-butanone, 2,2- VDL17 Ethyl formate 875Dimethyl-3-pentanone, 2,4- VDL18 Ethyl formate 875 Dichloroethane, 1,2-VDL19 Ethyl formate 875 Xylene, p- VDL20 Ethyl formate 875 Isoamylacetate VDL21 Ethyl formate 875 Toluene VDL22 Ethyl formate 875Ethylbenzene VDL23 Ethyl formate 875 Amylalcohol, tert- VDL24 Ethylformate 875 Chlorobenzene VDL25 Dimethyl Sulfoxide 500 Water VDL26Dimethyl Sulfoxide 500 Tetrahydrofuran VDL27 Dimethyl Sulfoxide 500Methyltetrahydrofuran, 2- VDL28 Dimethyl Sulfoxide 500 AcetonitrileVDL29 Dimethylacetamide N,N- 1000 Water VDL30 Dimethylacetamide N,N-1000 Tetrahydrofuran VDL31 Dimethylacetamide N,N- 1000Methyltetrahydrofuran, 2- VDL32 Dimethylacetamide N,N- 1000 AcetonitrileVDL33 Methanol 1000 Water VDL34 Methanol 1000 Tetrahydrofuran VDL35Methanol 1000 Methyltetrahydrofuran, 2- VDL36 Methanol 1000 Acetonitrile

Vapor Diffusion Onto Solids. For the vapour diffusion experiments,amorphous ponatinib hydrochloride was exposed to solvent vapours at roomtemperature for two weeks. The 8 ml vials with the amorphous API wereleft open and placed in a closed 40 ml vial with 2 ml of anti-solvent(see Table 13). After two weeks, the solids were analyzed by XRPD anddigital imaging. If the solids were liquefied by the vapours, thesamples were dried under vacuum (200 mbar or 10 mbar) before they wereanalyzed by XRPD and digital imaging.

TABLE 13 Experimental Conditions for the Vapor Diffusion Onto SolidsWeight Experiment Anti solvent (mg) VDS1 Methyl formate 21.4 VDS2Pentane 23.0 VDS3 Dichloromethane 26.4 VDS4 Methyl butyl ether, tert-22.7 VDS5 Chloroform 24.3 VDS6 Methanol 25.2 VDS7 Tetrahydrofuran 26.1VDS8 Diisopropyl ether 23.1 VDS9 Trifluoroethanol, 2,2,2- 24.5 VDS10Hexafluorobenzene 23.1 VDS11 Cyclohexane 22.4 VDS12 Acetonitrile 22.4VDS13 Dichloroethane, 1,2- 23.6 VDS14 Thiophene 22.1 VDS15 Ethyleneglycol dimethyl ether 22.7 VDS16 Diethoxymethane 20.5 VDS17 Heptane, n-24.9 VDS18 Trimethylpentane, 2,2,4- 27.3 VDS19 Water 21.7 VDS20Methylcyclohexane 27.5 VDS21 Nitromethane 23.6 VDS22 Dioxane, 1,4- 23.4VDS23 Trifluorotoluene, alpha, alpha, alpha- 22.4 VDS24Dimethyl-3-butanone, 2,2- 22.4 VDS25 Toluene 22.6 VDS26 Nitropropane, 2-23.5 VDS27 Octane, n- 26.7 VDS28 Butyl acetate 22.9 VDS29Dimethylcyclohexane, 1,2- 24.1 (cis\trans-mixture) VDS30 Cyclopentanone24.4 VDS31 Nitropropane, 1- 24.3 VDS32 Chlorobenzene 22.9 VDS33 Xylene,p- 24.0 VDS34 Fluorooctane, 1- 24.3 VDS35 Isoamyl acetate 24.9 VDS36Xylene, o- 23.7

In the crystallization experiments during these initial efforts, XRPDanalysis of the dry (and if applicable wet) samples obtained revealedthe presence of seven additional polymorphic forms in addition toamorphous materials and the starting material, Form A. The seven formsare designated HCl2, HCl2b, HCl3-class, HCl5, HCL5b, HCl6-class and themixture HCl1+HCl4.

The occurrence of the different forms obtained in Phase 2 of theseinitial efforts is presented in FIG. 2. XRPD patterns and digital imagesrepresentative of each form obtained in these Phase 2 experiments wereobtained. The characterization of the forms obtained in Phase 1 of theseinitial efforts is summarized in Table 14.

TABLE 14 Characterization of Certain Polymorphic Forms of ponatinibhydrochloride Crystallization Form Endotherms Purity Polymorphic formOccurrence^(a) solvent/mode^(b) nature^(c) (° C.)^(d) (%)^(e) Form A:HCl1^(g) (129, 50.8%)  Various/PSM, GRP, SLP Anhydrate 264.1 99.8 FormB: HCl2 (4, 1.5%) Water/PSM, SLP Nd^(f) Nd Nd Form C: HCl2b (6, 2.4) Water/GRP Hydrate 122.9, 99.8 (1:1.4) 158.2, 256.2 Form D: HCl3-Class(9, 3.5%) Toluene/PSM, GRP Nd Nd Nd Form F: HCl5 (1, 0.4%) Butylacelate/VDS Nd Nd Nd Form G: HCl5b (1, 0.4%) Butyl acelate/VDS + dryingNd Nd Nd Form H: HCl6-Class (5, 2.0%) Methanol/VDS Nd Nd Nd Form E:HCl1 + HCl4 (1, 0.4%) Hexafluorobenzene/GRP Nd Nd Nd ^(a)Occ: the totaloccurrence included 216 experiments carried out in Phase 2 for which 39samples were analyzed additionally wet or the mother liquor wasevaporated and analyzed giving a total of 254 materials characterized.For example, “(3, 1.2%)” correspond to 3 occurrences of the form out of254 measurements, giving a percentage of 1.2%. For 62 out of the 254measurements (9%), the product yield or the scattering intensity of someproducts was too low to identify the solid form, or the materials werewet. ^(b)Crystallization modes: cooling-evaporative (PSM), crashcrystallization with anti-solvent addition (AS), grinding (GRP), slurry(SLP), vapour diffusion onto solid (VDS) and vapour diffusion intosolution (VDL). Freeze-drying (FD) was used to produce amorphousmaterial (see Phase 1 experiments). QSA (quantitative solubilityexperiment), see Phase 1 experiments. ^(c)Solvation state assessed fromthe TGMS results. ^(d)Endotherms assessed from the DSC results.^(e)Chemical purity assessed from HPLC results. ^(f)Not determined inthis experiment. ^(g)Structure determined by single crystal analysis.

The polymorphic forms identified in these Phase 1 and Phase 2experiments and shown in FIG. 2 were assigned primarily on XRPDanalysis. In the course of this analysis, it was observed that somepatterns had similarities in the general fingerprint of the XRPD patternbut showed some small differences like peaks shifting or smalleradditional peaks. These types of patterns were clustered as a class ofpatterns (e.g. HCl3-Class). Based on the XRPD, it was concluded that thesimilarity between the XRPD patterns within a class is explained by thefact that these solid forms are isomorphic hydrates/solvates (similarcrystal packing but slightly different unit cell parameters caused bythe incorporation of the different solvents and water in the crystalstructure).

The classes of isomorphic solvates were designated by a number(HCl3-Class) or a number-letter combination (for example HCl2 andHCl2b). The class of isomorphic solvates/hydrates designated by aletter-number combination indicates that few sub-classes were observedfor this class in the experiment (example HCl2 and HCl2b). When morethan three sub-classes could be identified within the class, all XRPDpatterns corresponding to a class of isomorphic solvates/hydrates wereregrouped under one number (example HCl3-Class).

The isomorphic solvates within a certain class or between classesdesignated with the same number showed a higher degree of similarity oftheir XRPD patterns than in the case of the classes of isomorphicsolvates designated with different numbers. For these different classesof isomorphic hydrates/solvates, the larger differences in the XRPDpatterns reflect that the crystal structure packing is significantlydifferent.

In some XRPD patterns, one or two additional peaks were observedcompared to the identified forms. Since these peaks could not beassigned clearly to the known forms, they were indicated as “pluspeaks”.

Example 2 Further Discovery of Polymorphic Forms

Follow on efforts were undertaken to analyze single crystals of3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemono hydrochloride. Such efforts led to the discovery of five differentpseudo polymorphs with two of these additional polymorphic forms beingpreviously undiscovered. These two newly discovered polymorphic formsare designated herein as HCl7 (also referred to herein as “Form J”) andHCl 8 (also referred to herein as “Form K”). In these later experiments,three different crystallization techniques were used to grow singlecrystals of suitable size for analysis: (1) slow evaporation ofcrystallization solvent; (2) diffusion of anti-solvent into a solutionof3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidemono hydrochloride; and (3) temperature controlled crystallization. Intotal, 54 crystallization experiments were performed in these laterexperiments to attempt to grow single crystals of the hydrated form ofponatinib hydrochloride salt for structure determination.

With regard to temperature controlled crystallization, 24 experimentswere prepared with mixtures of alcohols and water (see Table 15). Foreach experiment, 10 mg of ponatinib hydrochloride was used. The mixturesof API and solvents were heated fast up to 80° C. and slowly cooled toroom temperature (0.1° C./min).

TABLE 15 Experimental Conditions of the Temperature ControlledCrystallization Experimentals Alcohol Water Water/ Exp [μl] [μl] AlcoholOutcome 1 MeOH (100) 900 9/1 White powder (trihydrate) 2 MeOH (200) 8008/2 White powder (trihydrate) 3 MeOH (300) 700 7/3 White powder(trihydrate) 4 MeOH (400) 600 6/4 White powder (trihydrate) 5 MeOH (500)500 5/5 White powder/yellow oil 6 MeOH (600) 400 4/6 White powder/yellowoil 7 MeOH (700) 300 3/7 White powder/yellow oil 8 MeOH (800) 200 2/8Oil/very small yellow crystals 9 MeOH (900) 100 1/9 Oil/very smallyellow crystals 10 EtOH (100) 900 9/1 White powder (trihydrate) 11 EtOH(200) 800 8/2 White powder (trihydrate) 12 EtOH (300) 700 7/3 Whitepowder (trihydrate) 13 EtOH (400) 600 6/4 White powder (trihydrate) 14EtOH (500) 500 5/5 White powder/yellow oil 15 EtOH (600) 400 4/6 Whitepowder/yellow oil 16 EtOH (700) 300 3/7 White powder/yellow oil 17 EtOH(800) 200 2/8 Oil/very small yellow crystals 18 EtOH (900) 100 1/9 Smallyellow crystals 19 TFE (100) 900 9/1 White powder/yellow oil 20 TFE(200) 800 8/2 White powder/yellow oil 21 TFE (300) 700 7/3 Yellow oil 22TFE (400) 600 6/4 Yellow oil 23 TFE (500) 500 5/5 Oil/very small yellowcrystals 24 TFE (600) 400 4/6 Oil/very small yellow crystals

With regard to vapor diffusion into solution, 25 experiments wereperformed. For each experiment, 10 mg of ponatinib hydrochloride wasdissolved in 1 ml of mixture of TFE/Water (10:90) or MeOH/Water (30:70).Each solution was placed in a 6 ml vial, which was inserted in a 20 mlvial containing 3 ml of anti-solvent. The vials were kept at roomtemperature for 2-4 weeks. The details are reported in Table 16.

TABLE 16 Experimental Conditions of the Vapor Diffusion Experiments ExpSolvent Anti-solvent Outcome 25 TFE/H₂O Ethyl Acetate No crystals 26TFE/H₂O n-Heptane No crystals 27 TFE/H₂O 2-Butanol No crystals 28TFE/H₂O MEK No crystals 29 TFE/H₂O o-Xylene White powder 30 TFE/H₂O THFNo crystals 31 TFE/H₂O Toluene Oil 32 TFE/H₂O Cyclohexane Oil 33 TFE/H₂O1,4-Dioxan No crystals 34 TFE/H₂O 2-MeTHF Oil 35 TFE/H₂O CyclohexanoneOil 36 TFE/H₂O Acetonitryle No crystals 37 MeOH/H₂O Propionitryle Oil 38MeOH/H₂O Toluene Light yellow crystals 39 MeOH/H₂O 1,4-Dioxan Nocrystals 40 MeOH/H₂O Diethylether Oil 41 MeOH/H₂O n-Heptane Oil 42MeOH/H₂O o-Xylene Light yellow crystals 43 MeOH/H₂O THF No crystals 44MeOH/H₂O Acetone No crystals 45 MeOH/H₂O Cyclohexane Oil 46 MeOH/H₂OButyl Acetate Light yellow needle crystals 47 MeOH/H₂O i-Propyl AcetateLight yellow needle crystals 48 MeOH/H₂O 2-Pentanol Cream plate crystals54 Ethanol Ethylacetate Yellow crystals

With regard to slow evaporation of solvents, 10 mg of ponatinibhydrochloride was placed in an 8 ml vial and 2 ml of solvent (mixture ofsolvents) was added. In those cases in which the solids did notdissolve, the vial was heated to 90° C. Subsequently, the mixture wasleft to cool slowly to room temperature (see Table 17). For the lastentry in Table 17, Exp. 53, the material had not completely dissolvedafter having been held several hours at 90° C.

TABLE 17 Experimental conditions of the slow evaporation experimentsTemperature Exp Solvents (ratio) [° C.] Outcome 49 TFE/H₂O (50:50) RTYellow crystals 50 EtOH/H₂O (70:30) 60 Yellow oil/small crystals 51MeOH/H₂O (70:30) 60 Yellow oil/small crystals 52 i-PrOH/H₂O (70:30) 60Yellow oil/small crystals 53 H₂O 90 White powder

Each of the polymorphic forms disclosed herein are made from specificcrystallization/solvent modes using ponatinib HCl as the startingmaterial. While the synthesis of ponatinib HCl has been describedpreviously (e.g., WO 2007/075869 and WO 2011/053938), the followingsynthesis of ponatinib HCl is provided at Example 6.

Example 3 Stress Test of Ponatinib Hydrochloride Form A

Form A is a crystalline, anhydrous solid that has been reproduciblyobtained from a range of solvents. Form HCl-1 is intrinsicallychemically stable, which directly correlates to the thermodynamicstability of the HCl 1 form. Form HCl-1 is stable to thermal, pressure,and humidity stress as well as exposure to some solvent vapors, and isthermodynamically stable. Numerous studies have been conducted toconfirm its stability in both the formulated (tablets) and unformulated(drug substance) state. The results of such studies are provided inTable 18 below:

TABLE 18 Stress Studies on Ponatinib Hydrochloride Form A Sample StressType Stress Conditions Analytical Results Drug Substance Thermal 70° C.for up to 72 hours TGMS, HPLC No change in form and XRPD approximately0.1% mass loss due to ethanol evaporation No apparent degradation 220°C. for 5 minutes TGMS, HPLC No change in form and XRPD approximately 1%mass loss due to ethanol evaporation No apparent degradation HumidityDVS cycling DVS, XRPD, No change in form (0-95-0% RH followed and TGMSNo change in DVS isotherm by 0-45% RH) Slight reduction in ethanolcontent by TGMS Exposure to humidity XRPD, TG No change in form (0%,22%, 40%, 75% and DSC and 97% RH) for 6 days Solvent Ethanol vapors atXRPD and Form HCl-1 remained vapors ambient temperature for digitalunchanged in samples of 2 weeks photographs 100% Form HCl-1 and 50:50mixture of HCl-1/amorphous ponatinib HCl Pressure Tablet press (drugXRPD and No changes observed in substance only): 4 ton digital ponatinibHCl for the (50 kN/cm²) and 8 ton photographs pressed drug-only tablets(100 kN/cm²)

Form HCl-1 is stable to thermal, pressure, and humidity stress as wellas exposure to some solvent vapors, and is the most thermodynamicallystable solid form isolated to date.

Experiments were carried out to test the physical stability of thecrystalline Form HCl1 as follows:

The crystalline Form HCl1 and a physical mixture of HCl1 and amorphousmaterial 50:50 were exposed to ethanol vapour for two weeks (see vapourdiffusion experiments). Tablets were prepared by subjecting thecrystalline Form HCl1 to a pressure of 50 and 100 kN/cm² (or 4 and 8ton/cm²) for 10 sec. Form A was stored in capsules for up to 17 monthsat ambient conditions. These samples were analyzed by high resolutionXRPD.

The results obtained are summarized in Table 19 and the XRPDmeasurements and digital images were obtained. They showed that withinthe stress conditions applied, the polymorphic Form HCl1 remainedunchanged, confirming its good physical stability.

TABLE 19 Results of follow-up work on Form A XRPD Experiment Stresscondition (Form) VDS37 Vapour diffusion (starting material HCl1 HCl1), 2ml Ethanol VDS38 Vapour diffusion (starting material HCl1 HCl1 and Am),2 ml Ethanol GEN12.1 10 sec, 50 kN HCl1 GEN12.2 10 sec, 50 kN, crushedtablet HCl1 GEN12.3 10 ses, 100 kN HCl1 GEN12.4 10 ses, 100 kN, crushedtablet HCl1 Capsule 2 mg sample 1 Ambient conditions for 17 months HCl1Capsule 2 mg sample 2 Ambient conditions for 17 months HCl1 Capsule 2 mgsample 3 Ambient conditions for 17 months HCl1

Example 4 Stability of Certain Polymorphic Forms

Samples of the 8 solid forms of HCl salt were chosen to study theirphysical stability. Two samples representative of each relevantpolymorphic forms of the HCl salt obtained were selected. Each samplewas re-analyzed by XRPD. The physical stability of the forms after beingstored at ambient conditions for 8 months. The results are summarizedbelow:

HCl1, HCl2b, HCl3-Class, HCl5b and HCl6-Class are physically stableunder the investigated conditions;

HCl2 converted to HCl2b (this conversion already occurred after storageof the sample under ambient conditions for 1 day);

HCl5 converted to HCl5b (this conversion already occurred followingdrying for 3 days under full vacuum);

The mixture HCl1+HCl4 converted to HCl1 after 8 months at ambientconditions.

TABLE 20 Physical stability of forms of HCl salt Form after storageunder ambient Polymorphic Crystallization Form conditions for 8 Startingform^(a) form obtained^(b) solvent/mode^(c) nature^(d) months SM HCl1 —Anhydrate HCl1 HCl1 or Am HCl2 Water/AS, PSM, SLP Nd^(e) HCl2b^(f) HCl1or Am HCl2b Water/AS, GRP, QSA Hydrate HCl2b (1:1.4) HCl1 or AmHCl3-Class aromatics/PSM, GRP, Nd HCl3-Class YDS Am HCl5 Butylacetate/VDS Nd HCl5b^(f) Am HCl5b Butyl acetate/VDS + drying Nd HCl5b AmHCl6-Class Methanol/VDS, VDL Nd HCl6-Class HCl1 HCl1 + HCl4Hexafluorobenzene/GRP Nd HCl1 ^(a)Starting material (SM): Form HCl1 oramorphous material (Am) obtained by freeze-drying. ^(b)As classified byXRPD after completion of the crystallization experiment.^(c)Crystallization modes: cooling-evaporative (PSM), crashcrystallization with anti-solvent addition (AS), grinding (GRP), slurry(SLP), vapour diffusion onto solid (VDS) and vapour diffusion intosolution (VDL). QSA (quantitative solubility experiment). ^(d)Solvationstate assessed from the TGMS results. ^(e)Nd = not determined. ^(f)HCl2and HCl5 converted to HCl2b and HCl5b after respectively storage at roomtemperature for a 1 day or drying under vacuum for 3 days.

Example 5 Preparation of Form A

Form A of ponatinib HCl is formed as a crystalline material by additionof a solution of HCl (1.0 equivalents) in ethanol to an ethanolicsolution of the ponatinib free base. The drug substance, ponatinib HCl,is crystallized in the last step of the drug substance synthetic processby addition of seed crystals which results in a very consistent andcharacteristic particle size and range for the drug substance. Ethanolcontent in the last 10 multi-kilogram scale batches of ponatinib HCl inthe HCl-1 form ranged from 0.8-1.2%.

No evidence of ethanol or water was found in the HCl-1 form; hence theForm A is an anhydrate. In addition, the crystal packing of the HCl-1form does not contain voids capable of accommodating ethanol or othersmall organic molecules. Additional studies to investigate the ethanolcontent and the removal of ethanol from ponatinib HCl during drying haveindicated that the ethanol appears to be associated with the surface ofthe crystals in Form A of ponatinib HCl.

Form HCl-1 is characterized by the consistent presence of residualethanol in all batches of drug substance at a level of approximately 1%by weight. Crystallographic studies and other studies have shown thatresidual ethanol is present (trapped) on the surface of the crystals,and is not part of the crystalline unit cell, and that HCl-1 is not anethanol solvate or channel solvate. Ethanol levels in the last tenmulti-kilogram scale drug substance batches have ranged from 0.8 to1.2%.

II. Polymorphic Forms of Ponatinib Free Base

The preparation of ponatinib free base starting material (AP23534) isshown and discussed below in the synthesis section of the disclosure(see Scheme 1). Preparation of amorphous free base is discussed in thesection of the disclosure entitled “Feasibility Study on Ponatinib FreeBase Compound” set out herein below.

Through XRPD analysis, a total of eleven polymorphic forms of ponatinibwere discovered, including anhydrate, and hydrate, solvate andisomorphic hydrate/solvate forms, beginning from ponatinib free basestarting material. The eleven new polymorphic forms are referred toherein as: Form A, Form B (or B-Class forms), Form C, Form D, Form E (orE-Class), Form F, Form G, Form H (or H-Class forms), Form I, Form J andForm K.

The anhydrate Form A (melting point ˜200° C.) was the predominantcrystalline form found in the screening. Form B includes four isomorphicsolvates, namely a 1:1 dioxane solvate, a 1:1 perfluorobenzene solvate,a 1:0.4 2-methylTHF solvate, and a 1:1 cyclohexanone solvate. Form Eincludes chloroform and dichloromethane isomorphic solvates. Form D is asolvated form (e.g. DMA). Form F is a monohydrated form. Form H includestwo isomorphic solvates, a 1:0.6 1-propanol solvate and a 1:0.932-methoxyethanol solvate.

The assignment of the forms obtained in the Phase 3 and Phase 4experiments was primarily based on the XRPD analysis. From this, itcould be observed that some patterns had similarities in the generalfingerprint of the XRPD pattern but showed some small differences suchas peaks shifting and/or small additional peaks. These types of patternswere clustered as a class of patterns (e.g. B-Class). Based on the XRPD,similarity between the XRPD patterns within a class can indicate thatthese solid forms are isomorphic hydrates/solvates (similar crystalpacking but slightly different unit cell parameters caused by theincorporation of the different solvents and water in the crystalstructure). The classes of isomorphic solvates were designated by aletter (B-Class).

In some XRPD patterns, one or more additional peaks were observedcompared to various identified forms. Since these peaks could not alwaysbe assigned clearly to the known forms, they were indicated as “pluspeaks” where appropriate, (e.g. “Form F plus peaks”).

The polymorph screen for ponatinib comprised six types ofcrystallization methods, carried out on millileter scale. The methodsincluded: crash-crystallization with anti-solvent addition; grinding;slurry experiments; vapor diffusion into solution; cooling-evaporativecrystallization; and vapor diffusion onto solids. These methods werediscussed above for preparation of the various ponatinib hydrochloridepolymorphs. Any differences in the methods when applied to the ponatinibfree base polymorphs will be discussed below.

The crystal structures of Form A and the two Form B solvates weredetermined by single crystal X-ray data analysis. These studies showedthe conformation adopted by Form A in the crystal structure and thesolvent inclusion in the two Form B solvates.

In general, these various crystalline forms of ponatinib disclosedherein have physical properties (such as high stability, etc.) that areadvantageous for the commercial preparation of solid dosage forms ascompared to amorphous ponatinib. The distinction between crystallineponatinib and amorphous ponatinib can be readily seen with the same typeof physical chemical data (e.g., DSC, XRPD, thermal analysis) that isused to distinguish the individual crystalline forms of ponatinibdisclosed herein.

FIGS. 48 and 49 provide tabular summaries are provided for ten of theeleven solid forms of ponatinib that include polymorphs andpseudo-polymorphs identified as Forms A through J disclosed herein.(Form K will be discussed separated herein below and is not part of thistabular summary). FIGS. 48 and 49 collectively provide origin,occurance, and various characteristics of the ponatinib polymorphs.

With reference to FIG. 48, “LC” refers to a low crystalline ponatinib(e.g. Form C) used as the starting material for various otherpolymorphs. “A” refers to Form A, the most abundant crystalline form ofponatinib, which can be used to prepare other forms via the variouscrystallization modes mentioned above. The footnotes appearing in thetable of FIG. 48 are as follows:

-   -   (a) As classified by XRPD after completion of the        crystallization experiments;    -   (b) Crystallization modes: cooling-evaporative (PSM), crash        crystallization with anti-solvent addition (AS), grinding (GRP),        slurry (SLP), vapour diffusion onto solid (VDS) and vapour        diffusion into solution (VDL). Freeze-drying (FD) was used to        produce low crystalline material (see Phase 3 experiments). QSA:        Quantitative Solubility Experiments (Phase 3);    -   (c) Occ: the total occurrence included 192 experiments carried        out in Phase 4 for which 61 samples were analyzed additionally        wet or the mother liquor was evaporated and analyzed giving a        total of 253 materials characterized. For example, “(6, 2.4%)”        correspond to 6 occurrences of the form out of 253 measurements,        giving a percentage of 2.4%. For 4 out of the 253 measurements        (1.6%), the product yield or the scattering intensity of some        products was too low to identify the solid form, or the        materials were wet;    -   (d) PO: preferred orientation effect; and    -   (e) Starting material: Form A or low crystalline (LC) material        obtained by freeze-drying.

With reference to the foregoing methodologies used in assessing theponatinib hydrochloride polymorphs, the polymorphs of3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamidefree base are discussed below.

Characteristics of Ponatinib Form A

The anhydrate Form A (same crystalline form as the starting material)was the predominant crystalline form discovered in screening. Thechemical structure of ponatinib Form A has been unambiguouslyestablished by single crystal X-ray crystallography. The observed solidform of ponatinib is the anhydrous crystalline solid Form A.

FIG. 50 represents the molecular structure and numbering scheme of FormA ponatinib free base compound (anhydrate) obtained from single-crystalX-ray diffraction. Based on this structure analysis, it was determinedthat Form A is an anhydrated form.

The crystallographic data for the anhydrate Form A (collected up toθ=26°) are listed in Table 21.

TABLE 21 Crystal Data and Structure Refinement for Ponatinib Form AIdentification code S10010A_AS37 Empirical formula C₂₉H₂₇F₃N₆O Formulaweight 532.57 T[K] 298(2) λ [Å] 0.71073 Crystal system Triclinic Spacegroup P-1 Unit cell dimensions a [Å] 9.182(2) b [Å] 10.187(2) c [Å]14.871(5) α [°] 95.746(6) β [°] 99.546(7) γ [°] 92.391(5) V [Å³]1362.4(6) Z 2 D_(c)[g/cm³] 1.298 μ [mm⁻¹] 0.096 F(000) 556 Crystal size[mm³] 0.43 × 0.25 × 0.20 θ range for data collection [°] 2.3 → 26Reflections collected 8369 Independent reflections 5340 [R_(int) =0.0253] Completeness to θ = 26° [%] 99.6 Max. and min. transmission0.9810 and 0.9598 Data/restraints/parameters 5340/0/357 Goodness-of-fiton F² 1.023 Final R indices [I > 2σ(I)] R1 = 0.0583, wR2 = 0.1371 Rindices (all data) R1 = 0.0932, wR2 = 0.1612 Extinction coefficient0.044(5)

FIG. 51 presents a comparison of the experimental XRPD pattern with thecalculated pattern (with FWHM=0.1°) based on the crystal structuredetermined for Form A. The close similarity of the two XRPD patternsindicates that the crystal structure of Form A is representative for thebulk material.

In the XRPD patterns shown in FIG. 51, at least one or all of thefollowing peaks in degrees two theta (2θ) is shown for crystalline FormA: 6.2; 8.8; 9.9; 11.2; 12.3; 12.9; 13.5; 13.8; 14.2; 14.4; 16.0; 16.4;17.2; 17.6; 18.0; 18.2; 19.3; 19.5; 19.8; 20.6; 21.5; 21.9; 22.2; 22.6;23.1; 24.0; 24.4; 25.1; 25.6; 25.9; 26.8; 27.4; 27.8; 29.1; and 29.8. Incertain embodiments, Form A is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 6.2; 12.3;13.8; 14.4; 16.0; 16.4; 17.2; 17.6; 18.2; 19.5; 19.8; 20.6; 21.5; 22.2;24.0; 25.9; 26.8; 27.4; and 27.8. In the XRPD patterns shown in FIG. 51,at least one or all of the following peaks in degrees two theta (2θ) isshown for Form A: 12.3; 13.8; 14.4; 17.6; 19.8; 20.6; 21.5; 22.6; and24.0. In certain embodiments, Form A is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 12.3;13.8; 17.6; 19.8; 20.6; 21.5; 22.6; and 24.0. In certain embodiments,the XRPD pattern of Form A shows two peaks, three peaks, four peaks orfive peaks selected from those above. In certain embodiments, thecrystalline Form A of ponatinib free base is characterized by an XRPDpattern substantially similar to the upper XRPD pattern (obtained) inFIG. 51. In certain embodiments, the crystalline Form A comprises anXRPD pattern with characteristic peaks expressed in degrees two-theta asshown in either the lower (simulated) or upper (obtained) pattern inFIG. 51.

With reference to FIG. 52, the melting point of ponatinib in theanhydrate Form A was determined by differential scanning calorimetry(DSC). Two samples of ponatinib, AP24534 Lot 1285.206A (treated with1-PrOH) and AP24524 Lot 1-PrOH Not Treated, were analyzed in a pin-holedcrucible in the temperature range of 30° C. to 350° C. at a heating rateof 10° C. per minute using dry N₂ gas purge. An endothermic event with apeak of 199.6° C. was observed, corresponding to the melting point ofponatinib Form A.

Characteristics of Ponatinib Form B (B-Class) Polymorphs

Characteristics of Ponatinib/1,4-Dioxane 1:1 Solvated Form B

Single-crystal X-ray diffraction analysis was employed to determine thecrystal structure of the 1:1 1,4-dioxane solvated Form B. FIG. 53represents the molecular structure and numbering scheme of the 1:11,4-dioxane solvated Form B obtained from single-crystal X-raydiffraction.

The crystallographic data for the 1:1 1,4-dioxane solvated Form B(collected up to 0=) 27.4° are listed in Table 22.

TABLE 22 Crystal Data and Structure Refinement for Ponatinib/1,4-dioxane1:1 solvated Form B Identification code S10010A_PSM32 Empirical formulaC₂₉H₂₇F₃N₆O•C₄H₈O₂ Formula weight 620.67 T [K] 298(2) λ [Å] 0.71073Crystal system Triclinic Space group P-1 Unit cell dimensions a [Å]8.311(2) b [Å] 12.691(4) c [Å] 15.779(6) α [°] 81.015(8) β [°] 88.388(8)γ [°] 82.209(7) V [Å³] 1628.7(9) Z 2 D_(c) [g/cm³] 1.266 A [mm⁻¹] 0.095F(000) 652 Crystal size [mm³] 0.40 × 0.36 × 0.10 θ range for datacollection [°] 3 → 27.4 Reflections collected 11721 Independentreflections 7312 [R_(int) = 0.0330] Completeness to θ = 27.4° [%] 99.0%Max. and min. transmission 0.9906 and 0.9631 Data/restraints/parameters7312/6/411 Goodness-of-fit on F² 1.032 Final R indices [I > 2σ(I)] R1 =0.0945, wR2 = 0.2337 R indices (all data) R1 = 0.1580, wR2 = 0.2815Extinction coefficient 0.023(5)

FIG. 54 presents the calculated pattern based on the crystal structuredetermined for Ponatinib/1,4-dioxane 1:1 solvated Form B.

In the XRPD pattern shown in FIG. 54, at least one or all of thefollowing peaks in degrees two theta (2θ) is shown forPonatinib/1,4-dioxane 1:1 solvated Form B: 5.6; 7.2; 9.8; 10.8; 12.1;12.5; 12.8; 14.5; 15.3; 15.8; 17.0; 17.3; 17.5; 18.5; 19.0; 19.5; 20.0;20.3; 21.1; 21.6; 22.4; 22.8; 23.5; 24.1; 24.5; 25.3; 26.0; 26.4; 27.0;27.5; 28.4; 30.8; and 32.0. In certain embodiments,Ponatinib/1,4-dioxane 1:1 solvated Form B is characterized by a XRPDpattern comprising one or more of the following peaks two theta (2θ):5.6; 10.8; 12.1; 14.5; 15.3; 15.8; 17.0; 17.3; 18.5; 19.0; 20.0; 20.3;21.6; 22.4; 24.5; and 26.0. In the XRPD pattern shown in FIG. 54, atleast one or all of the following peaks in degrees two theta (2θ) isshown for Ponatinib/1,4-dioxane 1:1 solvated Form B: 5.6; 12.1; 14.5;15.3; 15.8; 17.3; 18.5; 19.0; 20.3; 21.6; and 26.0. In certainembodiments, Ponatinib/1,4-dioxane 1:1 solvated Form B is characterizedby a XRPD pattern comprising one or more of the following peaks twotheta (2θ): 5.6; 14.5; 15.3; 15.8; 19.0; 20.3; and 26.0. In certainembodiments, the XRPD pattern of Ponatinib/1,4-dioxane 1:1 solvated FormB shows two peaks, three peaks, four peaks or five peaks selected fromthose given above. In certain embodiments, the Ponatinib/1,4-dioxane 1:1solvated Form B is characterized by an XRPD pattern substantiallysimilar to the XRPD pattern in FIG. 54. In certain embodiments, thePonatinib/1,4-dioxane 1:1 solvated Form B is crystalline.

Characteristics of Ponatinib/Perfluorobenzene 1:1 Solvated Form B

Single-crystal X-ray diffraction analysis was employed to determine thecrystal structure of the 1:1 perfluorobenzene solvated Form B. FIG. 55represents the molecular structure and numbering scheme of the 11:1perfluorobenzene solvated Form B obtained from single-crystal X-raydiffraction. The similarities between the unit cells and the crystalpacking of the 1,4-dioxane solvate and fluorobenzene solvate confirmedthat the Form B-class materials are isomorphic solvates.

The crystallographic data for the 1:1 perfluorobenzene solvated Form B(collected up to θ=27.6°) are listed in Table 23.

TABLE 23 Crystal Data and Structure Refinement forPonatinib/perfluorobenzene 1:1 solvated Form. Identification codeS10010A_VDL6 Empirical formula C₂₉H₂₇F₃N₆O•C₆H₅F Fw 628.67 T [K] 298(2)λ [Å] 0.71073 [Å] Crystal system Triclinic Space group P-1 Unit celldimensions a [Å] 8.182(3) b [Å] 12.863(4) c [Å] 15.877(6) α [°]80.412(13) β [°] 88.093(14) γ [°] 81.688(11) V [Å³] 1630.3(10) Z 2 D_(c)[g/cm³] 1.281 μ [mm⁻¹] 0.096 F(000) 656 Crystal size [mm³] 0.45 × 0.25 ×0.20 θ range for data collection [°] 3 → 27.6 Reflections collected10370 Independent reflections 7321 [R_(int) = 0.0315] Completeness to θ= 27.6° [%] 96.9 Max. and min. transmission 0.9811 and 0.9583Data/restraints/parameters 7321/0/381 Goodness-of-fit on F² 1.052 FinalR indices [I > 2σ(I)] R1 = 0.0885, wR2 = 0.2377 R indices (all data) R1= 0.1181, wR2 = 0.2691 Extinction coefficient 0.127(16)

FIG. 56 shows a comparison of the experimental XRPD pattern with thecalculated pattern (with FWHM=0.1°) based on the crystal structuredetermined for Form B 1:1 perfluorobenzene solvate. The close similarityof the two XRPD patterns indicates that the crystal structure of Form B1:1 perfluorobenzene is representative for the bulk material.

In the XRPD patterns shown in FIG. 56, at least one or all of thefollowing peaks in degrees two theta (2θ) is shown for Form B 1:1ponatinib/perfluorobenzene solvate: 7.0; 8.2; 9.8; 11.0; 11.5; 12.4;12.8; 124.0; 14.4; 15.3; 16.0; 16.6; 17.2; 18.2; 19.0; 19.5; 20.0; 20.1;21.1; 22.0; 22.5; 22.7; 23.5; 24.0; 24.5; 25.1; 26.0; 27.0; 27.8; 28.2;31.8; and 35.4. In certain embodiments, Form B 1:1ponatinib/perfluorobenzene solvate is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 5.6; 11.0;12.4; 12.8; 14.4; 15.3; 16.0; 16.6; 17.2; 18.2; 19.0; 20.1; 22.0; 22.5;22.7; 23.5; 24.5; 26.0; and 28.2. In the XRPD pattern shown in FIG. 56,at least one or all of the following peaks in degrees two theta (2θ) isshown for Form B 1:1 ponatinib/perfluorobenzene solvate: 5.6; 12.4;15.3; 16.0; 19.0; 20.1; 22.0; 22.5; 22.7; and 26.0. In certainembodiments, Form B 1:1 ponatinib/perfluorobenzene solvate ischaracterized by a XRPD pattern comprising one or more of the followingpeaks two theta (2θ): 5.6; 12.4; 15.3; 22.0; and 26.0. In certainembodiments, the XRPD pattern of Form B 1:1 ponatinib/perfluorobenzenesolvate shows two peaks, three peaks, four peaks or five peaks. Incertain embodiments, the Form B 1:1 ponatinib/perfluorobenzene solvateis characterized by an XRPD pattern substantially similar to the upperXRPD pattern in FIG. 56. In certain embodiments, the Form B 1:1ponatinib/perfluorobenzene solvate is characterized by an XRPD patternsubstantially similar to the lower XRPD pattern in FIG. 56. In certainembodiments, the crystalline Form B comprises an x-ray powderdiffraction pattern with characteristic peaks expressed in degreestwo-theta as shown in either the upper or lower pattern in FIG. 56.

Characteristics of Ponatinib/Cyclohexanone 1:1 Solvated Form B andPonatinib/2-methylTHF 1:0.4 Solvated Form B.

FIG. 57 shows a comparison of XRPD patterns of two other B-Class formsto the XRPD pattern obtained for Form A. The top pattern was obtainedfor GEN8.1, which is a 1:0.4 ponatinib/2-methylTHF solvate (B-Class,freeze drying, solvent=2-methylTHF). The middle pattern was obtained forQSA7.1, which is a 1:1 ponatinib/cyclohexanone solvate (B-Class,solvent=cyclohexanone). The bottom pattern is that obtained foranhydrate Form A.

In the upper XRPD pattern shown in FIG. 57, at least one or all of thefollowing peaks in degrees two theta (2θ) is shown for Form B 1:0.4ponatinib/2-methylTHF solvate: 5.6; 9.5; 10.5; 11.2; 12.0; 12.5; 13.5;14.0; 15.0; 15.5; 16.2; 16.8; 17.0; 18.1; 18.8; 20.1; 21.2; 22.1; 26.0;26.1; 27.5; and 28.2. In certain embodiments, Form B 1:0.4ponatinib/2-methylTHF solvate is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 5.6; 12.0;14.0; 15.0; 15.5; 16.8; 18.1; 20.1; and 26.0. In the upper XRPD patternshown in FIG. 57, at least one or all of the following peaks in degreestwo theta (2θ) is shown for Form B 1:0.4 ponatinib/2-methylTHF solvate:5.6; 12.0; 14.0; 20.1; 22.1 and 26.0. In certain embodiments, Form B1:0.4 ponatinib/2-methylTHF solvate is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 5.6; 14.0;20.1; and 26.0. In certain embodiments, the XRPD pattern of Form B 1:0.4ponatinib/2-methylTHF solvate shows two peaks, three peaks, four peaksor five peaks selected from those given above. In certain embodiments,the Form B 1:0.4 ponatinib/2-methylTHF solvate is characterized by anXRPD pattern substantially similar to the upper XRPD pattern in FIG. 57.In certain embodiments, the crystalline Form B comprises an x-ray powderdiffraction pattern with characteristic peaks expressed in degreestwo-theta as shown in the upper pattern in FIG. 57.

In the middle XRPD pattern shown in FIG. 57, at least one or all of thefollowing peaks in degrees two theta (2θ) is shown for Form B 1:1ponatinib/cyclohexanone solvate: 5.6; 9.5; 11.0; 12.0; 12.9; 14.0; 15.2;16.2; 16.8; 17.0; 18.1; 18.8; 19.5; 20.1; 21.8; 22.3; 23.0; 24.5; 26.1;27.5; 28.0; and 28.2. In certain embodiments, Form B 1:1ponatinib/cyclohexanone solvate is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 5.6; 11.0;12.0; 12.9; 14.0; 15.2; 16.8; 18.1; 18.8; 20.1; 21.8; 22.3; 24.5; and26.1. In the middle XRPD pattern shown in FIG. 57, at least one or allof the following peaks in degrees two theta (2θ) is shown for Form B 1:1ponatinib/cyclohexanone solvate: 5.6; 14.0; 15.2; 16.8; 20.1; 21.8;22.3; and 26.1. In certain embodiments, Form B 1:1ponatinib/cyclohexanone solvate is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 5.6; 14.0;15.2; 16.8; 20.1; 22.3; and 26.1. In certain embodiments, the XRPDpattern of Form B 1:1 ponatinib/cyclohexanone solvate shows two peaks,three peaks, four peaks or five peaks selected from those given above.In certain embodiments, the Form B 1:1 ponatinib/cyclohexanone solvateis characterized by an XRPD pattern substantially similar to the middleXRPD pattern in FIG. 57. In certain embodiments, the crystalline Form Bcomprises an x-ray powder diffraction pattern with characteristic peaksexpressed in degrees two-theta as shown in the middle pattern in FIG.57.

FIG. 58 is the DSC curve obtained for the B-Class 1:1ponatinib/cyclohexanone solvate (QSA7.1), showing endothermic events atT_(peak)=110.1° C. and T_(peak)=198.6° C.

FIG. 59 is the plot showing TGA and SDTA thermograms of B-Class 1:1ponatinib/cyclohexanone solvate (QSA7.1).

TGMS data for the B-Class 1:1 ponatinib/cyclohexanone solvate (QSA7.1)showed mass losses of 14.8% (cyclohexanone and water) and 0.2%(cyclohexanone) occurring within the temperature intervals of 50-160° C.and 160-210° C., respectively. The ponatinib/cyclohexanone ratio wasassessed from the TGMS data to be about 1.0/0.96.

Experiments to determine the purity of the B-Class 1:1ponatinib/cyclohexanone solvate (QSA7.1) were performed using HPLC. FromHPLC it was determined that the purity of the B-Class 1:1ponatinib/cyclohexanone solvate (QSA7.1) is 99.7460% (area percent).

FIG. 60 is the DSC curve obtained for the B-Class 1:0.4ponatinib/2-methylTHF solvate (GEN8.1), showing endothermic events atT_(peak)=67.1° C. and T_(peak)=197.5° C.

FIG. 61 is the plot showing TGA and SDTA thermograms of B-Class 1:0.4ponatinib/2-methylTHF solvate (GEN8.1).

TGMS data for the B-Class 1:0.4 ponatinib/2-methylTHF solvate (GEN8.1)showed mass losses of 3.1% (2-methylTHF), 1.9% and 1.0% (2-methylTHF)occurring within the temperature intervals of 40-90° C., 90-165° C. and165-215° C., respectively. The ponatinib/2-methylTHF ratio was assessedfrom the TGMS data to be about 1.0/0.4.

Experiments to determine the purity of the B-Class 1:0.4ponatinib/2-methylTHF solvate (GEN8.1) were performed using HPLC. FromHPLC it was determined that the purity of the B-Class 1:0.4ponatinib/2-methylTHF solvate (GEN8.1) is 99.5939% (area percent).

Characteristics of Ponatinib Form C (Low Crystalline) Polymorph

The low crystalline Form C can be obtained in the slurry experimentsfrom crystalline Form A in methanol as the solvent. Form C was found tocontain solvated methanol with the ratio of Ponatinib/methanol of about1:0.2.

FIG. 62 is the DSC curve obtained for low crystalline Form C (GEN3.1)showing an endothermic event at T_(peak)=95.9° C., an exothermic eventat T_(peak)=135.3° C., and an endothermic event at T_(peak)=198.1° C.

FIG. 63 is the plot showing TGA and SDTA thermograms of low crystallineForm C (GEN3.1).

TGMS data for Form C (GEN3.1) showed a mass loss of 1.3% (methanol)occurring within the temperature interval of 40-150° C. Theponatinib/methanol ratio was assessed from the TGMS data to be about1.0/0.2.

Form C was analyzed by X-ray powder diffraction (XRPD). FIG. 64 showsXRPD patterns of a XRPD overlay of starting material crystalline Form A(the bottom pattern) and low crystalline Form C (the upper pattern).

In the upper XRPD pattern shown in FIG. 64, at least one or all of thefollowing peaks in degrees two theta (2θ) is shown for Form C: 3.2;11.1; 11.7; 12.8; 13.3; 13.5; 14.2; 17.1; 18.2; 20.8; 22.3; and 26.5. Incertain embodiments, Form C is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 3.2; 12.8;14.2; 17.1; 18.2; 20.8; 22.3 and 26.5. In the XRPD pattern shown in FIG.64, at least one or all of the following peaks in degrees two theta (2θ)is shown for Form C: 3.2; 12.8; 14.2; and 18.2. In certain embodiments,the XRPD pattern of Form C shows two peaks, three peaks, four peaks orfive peaks selected from those given above. In certain embodiments, theForm C is characterized by an XRPD pattern substantially similar to theupper XRPD pattern in FIG. 64. In certain embodiments, the crystallineForm C comprises an x-ray powder diffraction pattern with characteristicpeaks expressed in degrees two-theta as shown in FIG. 64.

Experiments to determine the purity of Form C (GEN3.1) were performedusing HPLC. From HPLC it was determined that the purity of Form C ofponatinib is 99.5725% (area percent).

Characteristics of Ponatinib Form D Polymorph

Form D may be obtained from crystalline Form A by crash-crystallizationin N,N-dimethylacetamide (DMA) by anti-solvent addition. Produced inthis manner, Form D was found to be a DMA solvate with the ratio ofPonatinib/DMA of about 1:1.

FIG. 65 is the DSC curve obtained for Form D (GEN5.1R1) showingendothermic events at T_(peak)=103.3° C., T_(peak)=125.6° C., andT_(peak)=198.4° C.

FIG. 66 is the plot showing TGA and SDTA thermograms of low crystallineForm D (GEN5.1R1).

TGMS data for Form D (GEN5.1R1) showed a mass loss of 13.8%(N,N-dimethylaceamide) occurring within the temperature interval of40-140° C. The ponatinib/DMA ratio was assessed from the TGMS data to beabout 1.0/0.98.

Form D was analyzed by X-ray powder diffraction (XRPD). FIG. 67 showsXRPD patterns of a XRPD overlay (from bottom to top) of startingmaterial crystalline Form A; Form D (GEN5.1R1); and a remeasurementafter 3-days (GEN5.1R4), whereby the sample analyzed likely containsB-Class forms along with Form D.

In the middle XRPD pattern shown in FIG. 67, at least one or all of thefollowing peaks in degrees two theta (2θ) is shown for Form D: 6.2; 8.0;10.8; 11.5; 12.4; 13.5; 13.8; 14.5; 15.6; 16.5; 17.6; 18.5; 19.3; 19.8;20.1; 20.8; 21.6; 22.1; 23.8; 26.0; 27.1; and 29.6. In certainembodiments, Form D is characterized by a XRPD pattern comprising one ormore of the following peaks two theta (2θ): 6.2; 10.8; 12.4; 13.8; 14.5;15.6; 16.5; 18.5; 20.2; 20.8; 21.6; 26.0; and 27.1. In the middle XRPDpattern shown in FIG. 67, at least one or all of the following peaks indegrees two theta (2θ) is shown for Form D: 6.2; 12.4; 14.5; 15.6; 16.5;18.5; 20.2; 20.8; 21.6; 26.0; and 27.1. In certain embodiments, Form Dis characterized by a XRPD pattern comprising one or more of thefollowing peaks two theta (2θ): 6.2; 15.6; 16.5; 18.5; 20.2; 21.6; 26.0;and 27.1. In certain embodiments, the XRPD pattern of Form D shows twopeaks, three peaks, four peaks or five peaks selected from those givenabove. In certain embodiments, Form D of ponatinib is characterized byan XRPD pattern substantially similar to the middle XRPD pattern in FIG.67. In certain embodiments, the crystalline Form D comprises an x-raypowder diffraction pattern with characteristic peaks expressed indegrees two-theta as shown in FIG. 67.

Experiments to determine the purity of Form D were performed using HPLC.From HPLC it was determined that the purity of Form D of ponatinib is99.5056% (area percent).

Characteristics of Ponatinib Form E (E-Class) Polymorphs

The E-Class solvents are prepared from either crystalline Form A or lowcrystalline Form C in slurry and solubility experiments, using solventssuch as tetrahydrofuran (THF), chloroform and dichloromethane (DCM), orby vapor diffusion onto solids.

Based on thermal analyses, one sample representative of Form E wasassigned as a ponatinib/tetrahydrofuran (THF) 1:1 solvated form. Anothersample representative of Form E appears to be a chloroform solvate, butthis material was not characterized further other than by XRPD.

FIG. 68 is the DSC curve obtained for E-Class ponatinib/THF 1:1 solvate(GEN7.1) showing endothermic events at T_(peak)=95.9° C. andT_(peak)=198.1° C.

FIG. 69 is the plot showing TGA and SDTA thermograms of E-Classponatinib/THF 1:1 solvate (GEN7.1).

TGMS data for E-Class ponatinib/THF 1:1 solvate (GEN7.1) showed a massloss of 11.7% (THF) occurring within the temperature interval of 40-130°C. The ponatinib/THF ratio was assessed from the TGMS data to be about1.0/0.98.

The two above mentioned Class-E polymorphs were analyzed by X-ray powderdiffraction (XRPD). FIG. 70 shows XRPD patterns of a XRPD overlay (frombottom to top) of starting material crystalline Form A; E-Classponatinib/THF 1:1 solvate (GEN7.1); and E-Class ponatinib/chloroformsolvate (SLP3.1).

In the upper XRPD pattern shown in FIG. 70, at least one or all of thefollowing peaks in degrees two theta (2θ) is shown for E-Classponatinib/THF 1:1 solvate (GEN7.1): 6.2; 7.0; 10.0; 13.0; 15.1; 16.4;17.2; 18.5; 20.4; 20.5; 22.5; 24.4; 25.6; and 27.0. In certainembodiments, E-Class ponatinib/THF 1:1 solvate (GEN7.1) is characterizedby a XRPD pattern comprising one or more of the following peaks twotheta (2θ): 6.2; 7.0; 10.0; 15.1; 16.4; 17.2; 18.5; 20.4; 20.5 24.4; and27.0. In the upper XRPD pattern shown in FIG. 70, at least one or all ofthe following peaks in degrees two theta (2θ) is shown for E-Classponatinib/THF 1:1 solvate (GEN7.1): 6.2; 15.1; 16.4; 17.2; 18.5; 20.4;24.4; and 27.0. In certain embodiments, E-Class ponatinib/THF 1:1solvate (GEN7.1) is characterized by a XRPD pattern comprising one ormore of the following peaks two theta (2θ): 6.2; 15.1; 16.4; 20.4; and20.5. In certain embodiments, the XRPD pattern of E-Class ponatinib/THF1:1 solvate (GEN7.1) shows two peaks, three peaks, four peaks or fivepeaks selected from those given above. In certain embodiments, E-Classponatinib/THF 1:1 solvate is characterized by an XRPD patternsubstantially similar to the upper XRPD pattern in FIG. 70. In certainembodiments, the crystalline Form E comprises an x-ray powderdiffraction pattern with characteristic peaks expressed in degreestwo-theta as shown in the upper pattern in FIG. 70.

In the middle XRPD pattern shown in FIG. 70, at least one or all of thefollowing peaks in degrees two theta (2θ) is shown for E-Classponatinib/chloroform solvate (SLP3.1): 6.2; 7.0; 8.7; 9.8; 12.1; 12.5;13.0; 15.2; 16.4; 17.2; 18.5; 20.0; 21.0; 23.0; 24.4; 25.0; and 26.2. Incertain embodiments, E-Class ponatinib/chloroform solvate (SLP3.1) ischaracterized by a XRPD pattern comprising one or more of the followingpeaks two theta (2θ): 6.2; 7.0; 13.0; 15.2; 16.4; 17.2; 18.5; 20.0;21.0; 24.4; 25.0; and 26.2. In certain embodiments, the XRPD pattern ofE-Class ponatinib/chloroform solvate (SLP3.1) shows two peaks, threepeaks, four peaks or five peaks selected from those given above. Incertain embodiments, E-Class ponatinib/chloroform solvate ischaracterized by an XRPD pattern substantially similar to the middleXRPD pattern in FIG. 70. In certain embodiments, the crystalline Form Ecomprises an x-ray powder diffraction pattern with characteristic peaksexpressed in degrees two-theta as shown in the middle pattern in FIG.70.

Experiments to determine the purity of E-Class ponatinib/THF 1:1 solvate(GEN7.1) were performed using HPLC. From HPLC it was determined that thepurity of E-Class ponatinib/THF 1:1 solvate (GEN7.1) of ponatinib is99.5120% (area percent).

Characteristics of Ponatinib Form F Polymorph

Form F was formed from Form A in specific experimental conditions suchas in the presence of polar solvents. Analysis of Form F by TGMS showedthat Form F loses 3.3% of water in the first temperature range of25-140° C. From these results it could be concluded that the firstendotherm event observed corresponded to a dehydration process and thatForm F was a hydrated form, e.g. a 1:1 hydrate with water.

From the screening experiments, selected samples of pure Form F (6samples) and mixtures of Forms A and F (6 samples) were re-analyzed byXRPD after storage at ambient temperature for 4-months. The results areshown in Table 24 below.

TABLE 24 Samples of pure Form F and mixtures of Forms A + F re-analyzedby XRPD after 4-month storage. Cryst. Mode^(b) Form(s) Obtained (numberof samples Solvent (S), after re- form^(a) remeasured)^(c) anti-solvent(AS) analysis^(d) Form F AS (1 wet (S) 2-Methoxyethanol, A harvested)(AS) water AS (1) (S) Acetone, (AS) water A + F AS (2) (S) Methanol, F4-hydroxy-4-methyl-2- pentanone, (AS) Water SLP (1) 1,2-DimethoxyethaneVDL (1) (S) Methanol, (AS) Water A + F PSM (1) Water, A + F AS (1) (S)2-Methoxyethanol, (AS) water SLP (2), VDS (1, Water 1 wet harvested)^(a)As classified by XRPD after completion of the crystallizationexperiments. ^(b)Crystallization modes: cooling-evaporative (PSM), crashcrystallization with anti-solvent addition (AS), slurry (SLP), vapourdiffusion onto solid (VDS) and vapour diffusion into solution(VDL).^(c)From the screen, some experiments were selected to be remeasured byXRPD after storage for 4 months at ambient temperature. ^(d)Asclassified by XRPD after storage of the samples for 4 months at ambientconditions.

The results in Table 24 show that in most of the cases the polymorphicforms remained unchanged. The results obtained in the crashcrystallization with anti-solvent experiment (2-methoxyethanol/water)showed that when the sample was harvested wet, the Form F materialobtained converted to Form A after 4 months. Also in the anti-solventaddition experiment with acetone/water, Form F converted to a mixture ofForms A and F after 4 months.

FIG. 71 shows the TGA and SDTA plots obtained for Form F (AS16.2). FormF (AS16.2) showed a first endotherm followed by a recrystallization inthe temperature range of 130-140° C. The melting point of Form F(AS16.2) was observed at about 189° C.

As mentioned, TGMS data for Form F (AS16.2) showed a mass loss of 3.3%(water) occurring within the temperature interval of 25-140° C. Theponatinib/water ratio was assessed from the TGMS data to be about1.0/1.01 for Form F.

Form F (SLP10.1) was analyzed by X-ray powder diffraction (XRPD). InFIG. 83, a number of XRDP patterns are shown in stacked arrangement andwherein the pattern for Form F (SLP10.1) is the fifth pattern from thetop. This sample, (SLP10.1), was obtained in the slurry experimentsusing 1,2-dimethoxyethane as the solvent.

In the XRPD pattern shown as the pattern fifth from the top in FIG. 83,at least one or all of the following peaks in degrees two theta (2θ) isshown for ponatinib Form F: 7.2; 13.2; 14.1; 15.9; 18.1; 20.4; 21.1;22.0; 23.5; 24.2; 25.5; and 26.8. In certain embodiments, Form F ischaracterized by a XRPD pattern comprising one or more of the followingpeaks two theta (2θ): 7.2; 13.2; 14.1; 15.9; 18.1; 20.4; 23.5; 25.5 and26.8. In the XRPD pattern shown as the pattern fifth from the top inFIG. 83, at least one or all of the following peaks in degrees two theta(2θ) is shown for Form F: 7.2; 14.1; 18.1; 20.4; 25.5; and 26.8. Incertain embodiments, the XRPD pattern of Form F shows two peaks, threepeaks, four peaks or five peaks selected from those given above. Incertain embodiments, ponatinib Form F is characterized by an XRPDpattern substantially similar to the XRPD pattern fifth from the top inFIG. 83. In certain embodiments, the crystalline Form F comprises anx-ray powder diffraction pattern with characteristic peaks expressed indegrees two-theta as shown in the pattern fifth from the top in FIG. 83.

Characteristics of Ponatinib Form H (H-Class) Polymorphs

Characteristics of Ponatinib/1-Propanol 1:1 Solvated Form H

Solid recovered from a dissolution experiment with 1-propanol wasdetermined to be a 1-propanol solvate of Form H.

The DSC curve obtained for H-Class ponatinib/1-propanol solvate (SAS35)showed endothermic events appearing at T_(peak) of about 93° C. andT_(peak) of about 192° C.

The TGMS data for H-Class ponatinib/1-propanol solvate (SAS35) showed amass loss of 9.2% (1-propanol) occurring within the temperature intervalof 25-120° C. The ponatinib/1-propanol ratio was assessed from the TGMSdata to be about 1.0/0.9 for H-Class ponatinib/1-propanol solvate(SAS35). Another sample, (SAS30) showed a mass loss corresponding to a1:0.6 solvate, but this sample was later determined to have partiallyconverted back to crystalline anhydrate Form A, thus reducing theoverall solvent loss observed for the bulk sample.

H-Class solvate (SAS35) was analyzed by X-ray powder diffraction (XRPD)wherein at least one or all of the following peaks in degrees two theta(2θ) appeared: 6.1; 6.8; 10.0; 12.0; 13.2; 13.5; 16.0; 16.5; 16.0; 16.5;18.0; 19.0; 19.5; 20.4; 21.0; 22.5; 25.0; 25.5; 26.2; 27.0; and 27.5. Incertain embodiments, Form H is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 12.0;13.2; 13.5; 18.0; 25.0 and 25.5. In certain embodiments, the XRPDpattern of Form H shows two peaks, three peaks, four peaks or five peaksselected from those given above.

Characteristics of Ponatinib/2-Methoxyethanol 1:1 Solvated Form H

Ponatinib free base can form isomorphic solvates of Form H in otheralcohols. A 2-methoxyethanol solvate was obtained by a vapor diffusioninto liquid procedure, beginning with Form A as the starting materialand using 2-methoxyethanol as solvent. The purity of this form wasassessed to be 98.0%. TGMS confirmed it to be the 1:0.93ponatinib/2-methoxyethanol solvate, which desolvated at about 96° C.After desolvation, a melting point of about 198.8° C. was observed inthe DSC, which corresponds closely to the melting point of Form A.

The DVS experiment showed a loss of weight during desorption of about3.6%, which was not regained during sorption to 45% RH. XRPD analysis atthe end of the DVS experiments indicated no physical change. Whilepossible that partial desolvation occurred, the process did not causethe crystal structure to collapse (as indicated by the TG-MS about 12%weight loss is observed during the desolvation).

Form H, however, converted to Form A during 10 months of storage underambient conditions, and also after one week in a humidity chamber ataccelerated stress conditions (40° C., 75% RH).

FIG. 72 is the DSC curve obtained for Form H (VLD1, dried solid fromstock) showing endothermic events at T_(peak)=96.1° C. (desolvationevent) and T_(peak)=198.8° C. The endothermal event at 198.8° C. issuspected to be the melting event of Form A.

FIG. 73 is a characteristic overlay of TGA and SDTA thermograms of FormH (VLD1, dried solid from stock).

The DVS experiment for Form H (VLD1, dried solid from stock) showed aloss of weight of about 11.7% (2-methoxyethanol) in the temperaturerange of 25-120° C. From these results, the first endotherm eventobserved corresponded to a desolvation process and that Form H (VLD1,dried solid from stock) was a 1:0.93 ponatinib/2-methoxyethanol solvate.

FIG. 74 presents a series of XRPD patterns obtained for various samplesof Form H of ponatinib, along with the XRPD of Form A. In FIG. 74: Plot1 is Form H (VLD2 experiment, after 2-weeks and drying); Plot 2 is FormH (VLD1 experiment, after 2-weeks and drying); Plot 3 is Form H (VLD1experiment, dried solid from stock after DVS); Plot 4 is Form H (VLD1,dried solid from stock); Plot 5 is Form H (VLD19); and the bottom plotis the XRPD for Form A. The XRPD patterns shown as Plots 1-5 aresubstantially similar.

In the XRPD pattern shown as Plot 5 in FIG. 74, at least one or all ofthe following peaks in degrees two theta (2θ) is shown for ponatinibForm H: 6.2; 6.5; 10.1; 12.0; 13.2; 15.0; 15.5; 16.0; 16.5; 18.0; 19.1;19.6; 20.5; 21.1; 23.0; 23.7; and 25.5. In certain embodiments, Form His characterized by a XRPD pattern comprising one or more of thefollowing peaks two theta (2θ): 6.2; 12.0; 13.2; 16.0; 18.0; 19.1; 19.6;20.5; 21.1; 23.0; and 25.5. In the XRPD pattern shown as Plot 5 in FIG.74, at least one or all of the following peaks in degrees two theta (2θ)is shown for Form H: 6.2; 12.0; 18.0; and 25.5. In certain embodiments,the XRPD pattern of Form H shows two peaks, three peaks, four peaks orfive peaks selected from those above. In certain embodiments, ponatinibForm H is characterized by an XRPD pattern substantially similar to anyone of patterns 1-5 in FIG. 74. In certain embodiments, the crystallineForm H comprises an x-ray powder diffraction pattern with characteristicpeaks expressed in degrees two-theta as shown in any one of the patterns1-5 in FIG. 74.

Experiments to determine the purity of Form H (VLD1 dried solid fromstock) were performed using HPLC. From HPLC it was determined that thepurity of Form H of ponatinib (VLD1 dried solid from stock) is 98.0464%(area percent).

FIG. 75 is a characteristic FT-IR spectrum obtained from Form H ofponatinib (VLD1 dried from stock) (Plot 1) in overlay with the FT-IRspectrum obtained for Form A (Plot 2). Percent transmittance (%) isshown on the vertical axis and wavenumber (cm⁻¹) is shown on thehorizontal axis.

FIG. 76 is a characteristic FT-IR spectrum obtained from Form H ofponatinib (VLD1 dried from stock) (Plot 1) in overlay with the FT-IRspectrum obtained for Form A (Plot 2:), for the region of wavelength1750-600 nm. Percent transmittance (%) is shown on the vertical axis andwavenumber (cm⁻¹) is shown on the horizontal axis. This overlayidentifies several characteristic peaks for Form H, and also severalcharacteristic peaks for Form A. In this regard, some of thecharacteristic peaks for Form A in FIG. 76 (Plot 2) include: 1605; 1415;1295; 1250; 1150; 1145; 1110; 1100; 895; 855; and 790 cm⁻¹.

Characteristics of Ponatinib Form I Low Crystalline Polymorph

The low crystalline Form I was obtained by a freeze-drying technique indichloromethane (DCM).

Based on thermal analyses, Form I (GEN9.1) contains a slight level ofsolvated DCM, corresponding to a ponatinib/DCM ratio of about 1:0.03.

FIG. 77 is the DSC curve obtained for Form I (GEN9.1) showing anexothermic event at T_(peak)=100.1° C. and an endothermic event atT_(peak)=196.7° C.

FIG. 78 is the plot showing TGA and SDTA thermograms of Form I (GEN9.1).

TGMS data for Form I (GEN9.1) showed a mass loss of 0.5% (DCM) occurringwithin the temperature interval of 40-175° C. (slightly solvated). Theponatinib/DCM ratio was assessed from the TGMS data to be about1.0/0.03.

The Form I (GEN9.1) was analyzed by X-ray powder diffraction (XRPD).FIG. 77 shows XRPD overlay (from bottom to top) of starting materialcrystalline Form A and Form I (GEN9.1).

In the upper XRPD pattern shown in FIG. 79, at least one or all of thefollowing peaks in degrees two theta (2θ) is shown for Form I (GEN9.1):6.5; 8.2; 9.8; 14.3; 15.5; 17.5; 21.2; 23.1; and 26.5. In certainembodiments, Form I (GEN9.1) is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 6.5; 8.2;9.8; 14.3; 15.5; 17.5; 21.2; and 26.5. In the upper XRPD pattern of FIG.79, at least one or all of the following peaks in degrees two theta (2θ)is shown for Form I (GEN9.1): 6.5; 8.2; 15.5; 17.5; 21.2; and 26.5. Incertain embodiments, Form I (GEN9.1) is characterized by a XRPD patterncomprising one or more of the following peaks two theta (2θ): 8.2; and15.5. In certain embodiments, the XRPD pattern of Form I (GEN9.1) showstwo peaks, three peaks, four peaks or five peaks selected from thosegiven above. In certain embodiments, ponatinib Form I is characterizedby an XRPD pattern substantially similar to the top pattern in FIG. 79.In certain embodiments, the crystalline Form I comprises an x-ray powderdiffraction pattern with characteristic peaks expressed in degreestwo-theta as shown in the upper pattern in FIG. 79.

Experiments to determine the purity of Form I (GEN9.1) were performedusing HPLC. From HPLC it was determined that the purity of Form I(GEN9.1) of ponatinib is 99.5802% (area percent).

Characteristics of Ponatinib Form J Polymorph

Form J was obtained by a vapor diffusion onto solids method. The puritywas assessed to 96.5%. The TGMS analysis (weight loss of 11.4% thiopheneduring the interval 25-130° C.) confirmed that Form J “low crystalline”is a 1:0.82 ponatinib/thiophine solvate, which desolvates at 83.7° C.After desolvation, a melting point event occurs at about 197.3° C.,which may be the melting of Form A.

The DVS experiment showed a weight loss during desorption of about 1.3%.The weight appears not to be regained during the sorption phase, atleast up to 45% relative humidity (RH), (mass uptake about 0.33%). TheXRPD analysis at the end of the DVS experiments indicated that thematerial converted to Form A.

Low crystalline Form J also converted to Form A after 10 months ofstorage under ambient conditions, and after 1-week under stressconditions, (40° C., 75% RH).

Two samples of ponatinib Form J (designated VDS2 and VDS10 of screenS10010A) were analyzed by X-ray powder diffraction (XRPD). FIG. 78 showsXRPD overlay patterns (from top to bottom): Plot 6 is the XRPD patternfor Form A (VDS2, after stability study); Plot 7 is the XRPD pattern forForm J (VDS2); Plot 8 is the XRPD pattern of Form J (VDS10 of screenS10010A); and Plot 9 is another XRPD pattern of ponatinib Form A.

In the XRPD Plots 7 and 8 shown in FIG. 80, at least one or all of thefollowing peaks in degrees two theta (2θ) is shown for Form J ofponatinib: 5.8; 7.0; 12.1; 15.1; 16.8; 18.1; 18.6; 19.1; 19.5; 20.1;21.1; 21.8; 22.8; 25.0; 25.7; and 27.0. In certain embodiments, Form Jof ponatinib is characterized by a XRPD pattern comprising one or moreof the following peaks two theta (2θ): 5.8; 7.0; 12.1; 15.1; 16.8; 18.1;19.1; 19.5; 20.1; 21.1; 21.8; 22.8; 25.0; 25.7; and 27.0. In the upperXRPD pattern of FIG. 80, at least one or all of the following peaks indegrees two theta (2θ) is shown for Form J of ponatinib: 5.8; 7.0; 12.1;15.1; 16.8; 18.6; 19.1; 19.5; 21.8; 22.8; 25.0; 25.7; and 27.0. Incertain embodiments, Form J of ponatinib is characterized by a XRPDpattern comprising one or more of the following peaks two theta (2θ):5.8; 7.0; 12.1; 15.1; 18.6; 19.5; 21.8; 25.0; 25.7; and 27.0. In certainembodiments, the XRPD pattern of Form J of ponatinib shows two peaks,three peaks, four peaks or five peaks selected from those given above.In certain embodiments, Form J of ponatinib is characterized by an XRPDpattern substantially similar to either one of Plots 7 and 8 in FIG. 80.In certain embodiments, the crystalline Form J comprises an x-ray powderdiffraction pattern with characteristic peaks expressed in degreestwo-theta as shown in either one of Plots 7 and 8 in FIG. 80.

Experiments to determine the purity of Form J (VDS2) were performedusing HPLC. From HPLC it was determined that the purity of Form J (VDS2)of ponatinib is 96.4509% (area percent).

FIG. 81 is a characteristic FT-IR spectrum obtained from Form J (VDS2)of ponatinib (Plot 1) in overlay with the FT-IR spectrum obtained forForm A (Plot 2). Percent transmittance (%) is shown on the vertical axisand wavenumber (cm⁻¹) is shown on the horizontal axis.

FIG. 82 is a characteristic FT-IR spectrum obtained from Form J (VDS2)of ponatinib (Plot 1) in overlay with the FT-IR spectrum obtained forForm A (Plot 2), for the region of wavelength 1750-600 nm. Percenttransmittance (%) is shown on the vertical axis and wavenumber (cm⁻¹) isshown on the horizontal axis.

Characteristics of Ponatinib Form K Polymorph

Solid Form K was found in sample SAS58 (MSZW experiment): 25 mg/mL in1-propanol/acetonitrile 30/70. The TGMS thermogram showed negligiblemass loss (<0.04% in the temperature interval 25-175° C.) prior tomelting. From the SDTA signal, the melting point of Form K is 184° C.

The DSC curve obtained for ponatinib Form K showed an endothermic eventappearing at T_(peak) of about 184° C.

Ponatinib Form K was analyzed by X-ray powder diffraction (XRPD) whereinat least one or all of the following peaks in degrees two theta (2θ)appeared: 10.0; 11.0; 13.4; 14.6; 15.2; 16.0; 17.0; 17.5; 18.0; 19.6;20.9; 22.1; 22.8; 24.1; 24.8; 26.5; 27.1; 28.5; and 30.5. In certainembodiments, Form K is characterized by a XRPD pattern comprising one ormore of the following peaks two theta (2θ): 10.0; 11.0; 13.4; 14.6;15.2; 16.0; 19.6; 20.9; 22.1; 22.8; 24.1; 24.8; and 26.5. In certainembodiments, Form K is characterized by a XRPD pattern comprising one ormore of the following peaks two theta (2θ): 10.0; 11.0; 13.4; 14.6;15.2; 19.6; 22.1; 22.8; and 24.1. In certain embodiments, the XRPDpattern of Form K shows two peaks, three peaks, four peaks or five peaksselected from those above.

Overlay of XRPD Patterns for Selected Ponatinib Polymorphs

FIG. 83 is an overlay of the XRPD results obtained for selectedponatinib free base polymorphs. From bottom to top, the XRPD patternsshown were obtained for: Form A (SM); B-Class (QSAS7.1); Form C, lowcrystalline (GEN3.1); Form D (GEN5.1); E-Class (SLP3.1); Form F(SLP10.1); Form G (AS19.1), discussed herein below; Form H (VDL19.1);Form I, low crystalline (GEN9.1); and Form J, low crystalline (VDS10.1).

Characteristics of Ponatinib Form G Polymorph

FIG. 83 depicts ponatinib Form G, which was obtained by acrash-crystallization/anti-solvent process wherein the solvent used was3-methyl-1-butanol and the anti-solvent used was cyclohexane. PonatinibForm G was analyzed by X-ray powder diffraction (XRPD) wherein at leastone or all of the following peaks in degrees two theta (2θ) appeared:5.0; 6.5; 9.5; 12.0; 12.5; 14.0; 15.0; 16.5; 17.2; 18.4; 20.0; 21.0;22.8; 23.5; 24.6; and 29.5. In certain embodiments, Form G ischaracterized by a XRPD pattern comprising one or more of the followingpeaks two theta (2θ): 5.0; 6.5; 9.5; 14.0; 15.0; 16.5; 17.2; 18.4; 20.0;and 22.8. In certain embodiments, Form G is characterized by a XRPDpattern comprising one or more of the following peaks two theta (2θ):5.0; 6.5; 9.5; 14.0; 17.2; 18.4; 20.0; and 22.8. In certain embodiments,the XRPD pattern of Form G shows two peaks, three peaks, four peaks orfive peaks selected from those given above. In certain embodiments, FormG of ponatinib is characterized by an XRPD pattern substantially similarto the pattern forth from the top of overlaid patterns in FIG. 83. Incertain embodiments, the crystalline Form G comprises an x-ray powderdiffraction pattern with characteristic peaks expressed in degreestwo-theta as shown in the pattern forth from the top in FIG. 83.

Example 6 Discovery of Polymorphic Forms of Ponatinib

Initial efforts to discover polymorphic forms of ponatinib were dividedinto two phases. Phase 3 involved starting-material characterization,feasibility testing and solubility study to provide data for thesolvents selection for phase 4. Phase 4 involved 192 polymorph screeningexperiments at milliliter (ml) scale. These initial efforts led to thediscovery of eleven polymorphic forms of ponatinib free base, Form A,Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J,and Form K.

Phase 1: Starting Material Characterization

The compound ponatinib free base was obtained by the synthesis discussedherein below, which is characterized by an amide coupling reaction of anamine subunit and a methyl ester subunit. Approximately 20 grams of thefree base (combined from two batches, designated as F09-05575 andF09-05576) were obtained as a light yellow solid. This starting materialwas characterized by XRPD, digital imaging, DSC, TGMS and HPLC.

FIG. 84 shows the XRPD patterns of the free base starting material, withthe two patterns representing the two batches (F09-05575: lower pattern;and F09-05576: upper pattern) mentioned above.

FIG. 85 is the DSC curve for ponatinib free base starting material batchF09-05575, showing endothermic events at T_(peak)=182.6° C. andT_(peak)=199.0° C. (major). The major endotherm corresponds to themelting event, which may be accompanied by a desolvation process (asobserved in the TGA/SDTA trace for this batch).

FIG. 86 is the DSC curve for ponatinib free base starting material batchF09-05576, showing an endothermic event at T_(peak)=199.6° C. Theendotherm corresponds to the melting event, which may be accompanied bya desolvation process (as observed in the TGA/SDTA trace for thisbatch).

FIG. 87 is the plot showing TGA and SDTA thermograms of ponatinib freebase starting material batch F09-05575.

FIG. 88 is the plot showing TGA and SDTA thermograms of ponatinib freebase starting material batch F09-05576.

TGA and TGMS analyses showed mass loss in one single step for the batchF09-05575, (0.9% in the temperature interval of 25-210° C.) whereas atwo-step mass loss was observed in batch F09-05576 (0.3% mass loss inthe temperature interval of 25-120° C. and 0.9% in the interval 120-210°C.). The mass losses observed in both batches correspond to2-methyltetrahydrofuran (as confirmed by the m/z ratio's observed in theMS data). The presence of this solvent in residual quantities couldoriginate from the last synthesis steps of ponatinib free base compound.

Experiments to determine the purity of ponatinib free base compound wereperformed using HPLC. From HPLC it was determined that the purity ofbatch F09-05575 is 99.5166% (area percent), and the purity of batchF09-05576 is 99.6869% (area percent).

In various embodiments, alternative methods of preparing Form A gavesamples of varying crystallinity.

Alternative Ponatinib Form a Free Base Preparation Methods

Preparation 1

A M010578 sample from 180 g run ABL411057 (2-Me-THF, 1.1 equiv. ofaniline, 1.6 equiv. of KOtBu) was crystallized from neat 1-propanol,followed by a trituration of the 1-PrOH moist product in neatacetonitrile to give Form A in 99.39 a % purity.

Preparation 2

Two samples from 180 g run ABL411060 (2-Me-THF, 26° C. IT, 1.1 equiv. ofaniline, 1.6 equiv. of KOtBu) were obtained from a solution of M010578in 1-PrOH obtained after solvent swap from 2-Me-THF to 1-PrOH. The1-PrOH solution was split 9:1.

779.5 g (9 parts) of the above solution of M010578 in 1-PrOH wereallowed to crystallize at ambient temperature overnight. Afterfiltration, the moist filter cake was triturated in 160 g ofacetonitrile at 40° C., filtered and dried (50° C., 3 mbar) to obtain211.6 g of ponatinib free base Form A (99.87 a %).

260 g of acetonitrile were added to 86.6 g (1 part) of the abovesolution of M010578 in 1-PrOH. The suspension was filtered after 1 h,the filter cake washed with ACN/1-PrOH (3:1 v/v), and dried to obtain25.6 g free base (99.27 a %). Crystallization and isolation from1-propanol followed by a trituration in acetonitrile gave product ofhigher HPLC purity than isolation by precipitation from a mixture ofACN/1-PrOH.

Phase 1: Solubility Study

Quantitative solubility testing was performed on ponatinib free basestarting material, employing a set of 20 solvents. Slurries wereprepared with an equilibration time of 24 hours after which the slurrieswere filtered. The solubility was determined from the saturatedsolutions by HPLC. The residual solids were characterized by XRPD. Theresults are summarized in Table 25 below.

TABLE 25 Solubility Study of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide Solubility XRPDExperiment Solvent name (mg/ml) Form¹ QSA1 Diethylene glycoldiethylether 32.35 A QSA2 Diethyl Ether 0.95 A QSA3 Dimethyl Sulfoxide124.45 A QSA4 Isobutyl isobutyrate 2.5 A QSA5 Dimethylacetamide N,N- OR³A QSA6 Pentyl ether UR, <0.21² A QSA7 Cyclohexanone 30.78 B-Class QSA8Xylene, p- 0.8 A QSA9 Isobutanol 20.95 A QSA10 Butyl acetate 8.04 AQSA11 Heptane, n- UR, <0.21² A QSA12 Water UR, <0.21² A QSA13Trifluoroethanol 2,2,2- OR³ A QSA14 Hexafluorobenzene 0.21 A QSA15isopropanol 11.23 A QSA16 Isopropyl acetate 5.8 A QSA17 Dichloroethane1,2- 10.8 A QSA18 Acetonitrile 1.53 A QSA19 Tetrahydrofuran 146.17 AQSA20 Methanol 42.95 A QSA21 Water UR, <0.21² A QSA22 Water UR, <0.21² AQSA23 Heptane, n- UR, <0.21² A QSA24 Heptane, n- UR, <0.21² A QSA27Dimethyl sulfoxide 139.72 A QSA28 Dimethyl sulfoxide 138.56 A QSA29Acetonitrile 1.15 A QSA30 Acetonitrile 1.38 A QSA312-Methyltetrahydrofuran 35.5 A QSA32 Ethanol 25.2 A ¹The solid formobtained from the slurry was assessed based on the XRPD analysis. ²UnderRange, lower than detection limit, the concentration is lower than 0.21mg/mL. ³Over Range, the material was dissolved, the concentration ishigher than 200 mg/mL.

The materials obtained from in 19 out of 22 different solubilityassessments were the same polymorph as the starting material free base,designated Form A. The solid from the slurry with cyclohexanone shows adifferent XRPD, which was designated the B-Class of forms. Form B wasfurther characterized as four solvates, as discussed herein above.

Feasibility Study on Ponatinib Free Base Compound

Feasibility tests were performed to attempt to obtain amorphous freebase material that could be employed in some crystallization techniquesof Phase 4. Two techniques were employed, i.e., grinding andfreeze-drying. The results are presented below.

Grinding. As summarized in Table 26 below, two grinding experiments wereperformed with two different durations at a frequency of 30 Hz. After 60or 120 minutes of grinding, the material remained crystalline, (Form A).

TABLE 26 Grinding Feasibility Sudy of Ponatinib Free Base. Time FormExperiment (min) (XRPD) GEN1.1 60 A GEN1.2 120 A

Freeze-drying. Eight freeze-drying experiments were performed withponatinib free base compound. These experiments are summarized in Table27 below.

TABLE 27 Freeze-drying feasibility study of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide mono hydrochloride Solvent Experi-content Purity ment Solvent Form (XRPD) (%)¹ (%)² GEN2 Dimethylsulfoxide — (not dry) — — GEN3 Methanol C low crystalline 1.3 99.6 GEN42,2,2-Trifluoroethanol/ Am gel — — Water 90/10 GEN5N,N-Dimethylacetamide/ D 13.8  99.5 Water 90/10 GEN62,2,2-Trifluoroethanol Am gel — — GEN7 Tetrahydrofuran E-Class 11.7 99.5 GEN8 2-Methyltetrahydrofuran B-Class 6.0 99.6 GEN9 DichloromethaneI low crystalline 0.5 99.6 ¹Based on the TGMS results; ²Chemical puritydetermined by HPLC.

With solvents such as 2,2,2-trifluoroethanol (TFE) and TFE/watermixtures, amorphous material was obtained. In the experiments carriedout in 2-methyltetrahydrofuran, DMA/water 90:10 and THF, three newcrystalline forms were observed and were designated B-Class, D andE-Class. The B-Class and E-Class of forms were also observed in thescreen Phase 4, for which the results suggested that they are isomorphicstructures. In the remaining experiments performed in methanol anddichloromethane, two low crystalline materials were produced (Form C lowcrystalline and Form I low crystalline, respectively).

The new crystalline forms were further analyzed by DSC, TGMS and HPLC todetermine their characteristics. Form D and Form E were identified assolvates (1:1 API/DMA and 1:1 API/THF, respectively).

The low crystalline materials obtained from methanol (C low crystalline)and dichloromethane (I low crystalline) had a limited amount of residualsolvent (1.3% in the temperature interval 40° C.-150° C. and 0.5% in theinterval 40° C.-175° C., respectively).

Since the freeze-drying procedure in methanol was not optimal to producelow crystalline material, the procedure in dichloromethane was selectedto produce this material to be used in the cooling/evaporativecrystallizations and vapour diffusion onto solids experiments of Phase4.

Based on the results of the feasibility studies and the solubilitybehaviour of ponatinib free base, the solvents for the Phase 4experiments were selected.

Solvent Assessment

In order to select the screening solvents and to determine theconcentration range to be used in the screen, quantitative solubilitytesting was performed on the free base starting material batchF09-05575. This screen employed a set of 20 solvents. For each solvent,a standard 1.8 ml screw cap vial was charged with 40 mg of the startingmaterial, 200 μl of the solvent and a magnetic stirring bar. The vialswere then closed and equilibrated at 25° C. for 24 h while stirring. Theresulting mixtures (slurries) were filtered (0.5 micron) and theisolated mother liquors diluted to two dilutions selected according tothe calibration curve. Quantities of the API in the diluted solutionswere determined via HPLC analysis (DAD). The calibration curve wasobtained from two independently prepared stock solutions of the freebase compound in 2,2,2-trifluoroethanol.

Subsequently to the solubility determination, the residual solvent wasevaporated from each vial (slurry) under vacuum at ambient temperature.All of the resulting residues were analyzed by X-ray powder diffractionto assay for new crystalline forms.

Feasibility Study

The experimental conditions of the feasibility study on the free basecompound are summarized in Table 28 below. Following the experiments,HPLC analysis was performed to determine the purity and thermal analysisto determine the thermal behaviour of the forms.

TABLE 28 Condition Applied for the Feasibility Study on Ponatinib FreeBase Compound. Solvent Experi- content Purity ment Solvent Form (XRPD)(%)¹ (%)² GEN2 Dimethyl sulfoxide — (not dry) — — GEN3 Methanol C low1.3 99.6 crystalline GEN4 2,2,2-Trifluoroethanol/ Am gel — — Water(90/10) GEN5 N,N-Dimethylacetamide/ D 13.8  99.5 Water (90/10) GEN62,2,2-Trifluoroethanol Am gel — — GEN7 Tetrahydrofuran E-class 11.7 99.5 GEN8 2-Methyltetrahydrofuran B-class 6.0 99.6 GEN9 DichloromethaneI low crystalline 0.5 99.6 ¹Solvent content assessed by TGA; ²Purityassessed by HPLC

Polymorph Screening Experimental Design and Protocols

The polymorph screening experiments for the ponatinib free base compoundwere carried out at milliliter (ml) scale using 192 different conditionsin which the following six different crystallization procedures wereapplied: cooling-evaporation, anti-solvent addition, grinding, slurry,vapor diffusion into solutions and vapor diffusion onto solids.

Cooling-Evaporative Crystallization Experiments

The 24 cooling-evaporative experiments at ml scale were performed in 8ml vials, employing 24 different solvents and 1 concentration. In eachvial, 25 mg of ponatinib free base was liquid dosed (withdichloromethane). The samples were freeze dried to obtain powdery lowcrystalline material. Then, the screening solvent was added to reach aconcentration of circa 60 mg/ml, (see Table 29 below). The vials wereclosed and a temperature profile was obtained as described in Table 30below. The mixtures were cooled to 5° C. and held at that temperaturefor 48 h before placing the vials under vacuum. The solvents wereevaporated for several days at 200 mbar or 10 mbar and analyzed by XRPDand digital imaging.

TABLE 29 Experimental Conditions for the 24 mL Experiments using theCooling-Evaportaion Method. Weight Volume Experiment Solvent (mg) (□olPSM25 Chloroform 21.8 380 PSM26 Methyl butyl ether, tert- 21.9 380 PSM27Methanol 22.8 380 PSM28 Cyclohexane 22.7 380 PSM29 Acetonitrile 22.0 380PSM30 Heptane, n- 22.3 380 PSM31 Methanol/Chloroform (50/50) 22.7 380PSM32 Dioxane, 1,4- 22.2 380 PSM33 Butyl acetate 21.0 380 PSM34Chlorobenzene 21.4 380 PSM35 Xylene, m- 21.2 380 PSM36 Ethanol 20.4 380PSM37 Water 32.8 500 PSM38 Methanol/Acetonitrile (50/50) 27.4 450 PSM39Acetonitrile/Chloroform (50/50) 25.8 450 PSM40Cyclohexane/Tetrahydrofuran (50/50) 22.9 400 PSM41 Methyl butyl ether,tert-/Xylene, m- 22.7 400 (50/50) PSM42 Cyclohexane/Dioxane, 1,4-(50/50) 23.1 400 PSM43 Cyclohexane/N-methyl-2-pyrrolidone 22.7 400(50/50) PSM44 Heptane, n-/Cyclohexane (50/50) 22.8 400 PSM45Tetrahydrofuran/N-methyl-2- 21.4 350 pyrrolidone (50/50) PSM46Tetrahydronaphthalene, 1,2,3,4-/ 21.3 350 Methylcyclohexane (50/50)PSM47 Butyl acetate/N-methyl-2-pyrrolidone 20.8 350 (50/50) PSM48Tetrahydronaphthalene, 1,2,3,4-/ 19.9 350 Cumene (50/50)

TABLE 30 Temperature Profile used for the (24) Cooling-EvaporativeExperiments. Experiments Heating rate T_(initial) Hold Cooling rateT_(final) Hold PSM1-24 10 60 60 1 5 48

Crash-Crystallization with Anti-Solvent Addition

For the crash-crystallization experiments, 48 different crystallizationconditions were applied, using 23 different solvents and 18 differentanti-solvents (see Table 31 below). For each solvent, a stock solutionwas prepared, the concentration of ponatinib free base in each casebeing that attained at saturation at ambient temperature afterequilibration for 17 hours before filtering into a set of 8 ml vials. Toeach of these vials, a different anti-solvent was added, using a solventto anti-solvent ratio of 1:0.25. In those cases where no precipitationoccurred, this ratio was increased to 1:4 with a waiting time of 60minutes between the additions. Solids precipitated in the waiting timebetween the anti-solvent additions were separated by centrifugation. Ifno solids were obtained, the solvents were completely evaporated undervacuum at room temperature. If solids were obtained, they were analysedby XRPD and digital imaging.

TABLE 31 Experimental Design of the Crash-Crystallization Experimentswith Anti-Solvent Addition. Ratio Exper- S:AS iment Solvent Anti-Solvent(1:x) AS1 Acetone Cyclohexane 4 AS2 Ethyl formate Methyl butyl ether, 4tert- AS3 Ethyl formate Chloroform 4 AS4 Ethyl formate Diethoxymethane 4AS5 Acetone Water 1 AS6 Tetrahydrofuran Cyclohexane 1 AS7 Ethyl formateIsoamyl acetate 4 AS8 Ethylene glycol dimethyl Chloroform 4 ether AS9Butanone, 2- Cyclohexane 4 AS10 Dioxane, 1,4- Chloroform 4 AS11 Ethylformate Anisole 4 AS12 Methyltetrahydrofuran, 2- Cyclohexane 0.25 AS13Ethylene glycol dimethyl Diisopropyl ether 1 ether AS14 TetrahydrofuranToluene 1 AS15 Dioxane, 1,4- Diisopropyl ether 4 AS16 Methanol Water 1AS17 Dioxane, 1,4- Cyclohexane 1 AS18 Ethylene glycol dimethylCyclohexane 1 ether AS19 Methyl-1-Butanol, 3- Cyclohexane 4 AS20Methyltetrahydrofuran, 2- Methylcyclohexane 1 AS21 Methyl-2-butanone, 3-Trimethylpentane, 1 2,2,4- AS22 Amylalcohol, tert- Trimethylpentane, 12,2,4- AS23 Dioxane, 1,4- Methylcyclohexane 1 AS24 Ethylene glycoldimethyl Heptane, n- 1 ether AS25 Ethyl formate Xylene, p- 1 AS26Dioxane, 1,4- Heptane, n- 1 AS27 Ethyl acetate Cyclohexane 4 AS28Cyclohexanone Cyclohexane 4 AS29 Diethyleneglycol-dimethylether Water0.25 AS30 Cyclohexanone Water 4 AS31 Ethoxyethanol, 2- Water 0.25 AS32Hydroxy-4-methyl-2-pentanone, Water 1 4- AS33 Methoxyethanol, 2- Water 1AS34 Dimethylformamide, N,N- Water 0.25 AS35 Dimethylacetamide, N,N-Heptane, n- 4 AS36 Isoamyl acetate Diethoxymethane 4 AS37 PropionitrileTrimethylpentane, 4 2,2,4- AS38 Amylalcohol, tert- Cumene 4 AS39Ethylene glycol dimethyl Anisole 4 ether AS40 Butyl acetate Heptane, n-4 AS41 Amylalcohol, tert- Methylcyclohexane 4 AS42 ButyronitrileChlorobenzene 4 AS43 Butyl acetate Xylene, p- 4 AS44 CyclohexanoneDiethyl carbonate 4 AS45 Butyl acetate Dimethyl-4-heptanone, 4 2,6- AS46Dimethylformamide, N,N- Xylene, p- 4 AS47 Cyclohexanone Nonane, n- 4AS48 Ethoxyethanol, 2- Dimethyl-4-heptanone, 4 2,6-

Grinding Experiments

The drop-grinding technique uses a small amount of solvent added to theponatinib free base material which is ground in a stainless steelgrinder jar with 2 stainless steel grinding balls. In this manner, theeffect of 24 different solvents (see Table 32 below) was investigated.Typically, 30 mg of starting material was ground and analyzed.

TABLE 32 Experimental Conditions for the Grinding Experiments Exper-Weight Volume iment Solvent (mg) (ul) GRP1 Hexafluorobenzene 28.6 10GRP2 Cyclohexane 31.0 10 GRP3 Acetonitrile 30.2 10 GRP4 Ethylene glycoldimethyl ether 30.5 10 GRP5 Diethoxymethane 29.7 10 GRP6 Heptane, n-30.4 10 GRP7 Trimethylpentane, 2,2,4- 30.1 10 GRP8 Water 29.7 10 GRP9Nitromethane 29.9 10 GRP10 Dioxane, 1,4- 30.9 10 GRP11 Trifluorotoluene,alpha, 29.5 10 alpha, alpha- GRP12 Toluene 29.7 10 GRP13 Nitropropane,2- 29.9 10 GRP14 Nitropropane, 1- 29.5 10 GRP15 Xylene, p- 30.7 10 GRP16Fluorooctane,1- 29.6 10 GRP17 Isoamyl acetate 24.1 10 GRP18 Xylene o-30.2 10 GRP19 Nonane, n- 29.5 10 GRP20 Cyclohexanone 30.6 10 GRP21Diethyleneglycol-dimethylether 29.9 10 GRP22 Butylbenzene, sec- 29.7 10GRP23 Decane 30.1 10 GRP24 Limonene, (R)-(+)- 29.4 10

Slurry Experiments

A total of 48 slurry experiments were performed with ponatinib freebase, 24 solvents at each of 10° C. and 30° C., for 2 weeks. Table 33below summarizes the experimental conditions. The experiments arecarried out by stirring a suspension of the material in a solvent at acontrolled temperature. At the end of the slurry time, the vials werecentrifuged and solids and mother liquids separated. The solids werefurther dried under full vacuum at room temperature and analyzed by XRPDand digital imaging.

TABLE 33 Experimental Conditions for the Slurry Experiments Temper-Weight Volume ature Experiment Solvent (mg) (ul) (° C.) SLP1 Methylbutyl ether, tert- 24.3 250 10 SLP2 Methyl acetate 26.3 250 10 SLP3Chloroform 55.7 250 10 SLP4 Methanol 23.4 250 10 SLP5 Tetrahydrofuran27.1 250 10 SLP6 Hexane, n- 24.4 250 10 SLP7 Ethanol 26.9 250 10 SLP8Cyclohexane 25.1 250 10 SLP9 Acetonitrile 24.8 250 10 SLP10Dimethoxyethane, 1,2- 24.4 200 10 SLP11 Isopropyl acetate 23.9 250 10SLP12 Heptane, n- 25.7 250 10 SLP13 Water 28.1 250 10 SLP14Methylcyclohexane 27.8 250 10 SLP15 Dioxane, 1,4- 25.5 250 10 SLP16Isobutanol 24.2 250 10 SLP17 Toluene 27.4 250 10 SLP18 Butyl acetate27.0 250 10 SLP19 Hexanone 2- 24.6 250 10 SLP20 Chlorobenzene 27.8 25010 SLP21 Ethoxyethanol, 2- 25.6 250 10 SLP22 Xylene, m- 24.4 250 10SLP23 Cumene 25.0 250 10 SLP24 Anisole 25.1 250 10 SLP25 Methyl butylether, tert- 25.8 250 30 SLP26 Methyl acetate 25.1 250 30 SLP27Chloroform 84.8 250 30 SLP28 Methanol 25.0 250 30 SLP29 Tetrahydrofuran23.6 250 30 SLP30 Hexane, n- 20.4 250 30 SLP31 Ethanol 23.9 250 30 SLP32Cyclohexane 28.3 250 30 SLP33 Acetonitrile 24.1 250 30 SLP34Dimethoxyethane, 1,2- 25.2 200 30 SLP35 Isopropyl acetate 23.9 250 30SLP36 Heptane, n- 24.1 250 30 SLP37 Water 24.0 250 30 SLP38Methylcyclohexane 25.3 250 30 SLP39 Dioxane, 1,4- 24.6 250 30 SLP40Isobutanol 26.7 250 30 SLP41 Toluene 26.3 250 30 SLP42 Butyl acetate24.1 250 30 SLP43 Hexanone 2- 26.4 250 30 SLP44 Chlorobenzene 25.3 25030 SLP45 Ethoxyethanol, 2- 26.6 250 30 SLP46 Xylene, m- 24.7 250 30SLP47 Cumene 23.8 250 30 SLP48 Anisole 24.1 250 30Vapor Diffusion into Solutions

For the vapor diffusion experiments, saturated solutions of ponatinibfree base were exposed to solvent vapors at room temperature for twoweeks. A volume of saturated solution was transferred to an 8 ml vialwhich was left open and placed in a closed 40 ml vial with 2 ml ofanti-solvent (see Table 34 below). After two weeks, the samples werechecked on solid formation. If solids were present the liquid wasseparated from the solid. The samples were dried under vacuum (200 mbaror 10 mbar) before they were analyzed by XRPD and digital imaging.

TABLE 34 Experimental Conditions for the Vapor-Diffusion into SolutionsVolume solution Experiment Solvent of solution (ul) Anti-Solvent VDL1Dichloromethane 900 Cyclohexane VDL2 Ethyl formate 1000 Chloroform VDL3Acetone 1000 Water VDL4 Tetrahydrofuran 450 Cyclohexane VDL5 Ethylformate 1000 Isoamyl acetate VDL6 Tetrahydrofuran 450 Fluorobenzene VDL7Methyltetrahydrofuran, 2- 500 Cyclohexane VDL8 Ethyl acetate 1000Trimethylpentane, 2,2,4- VDL9 Ethylene glycol dimethyl 500 Diisopropylether ether VDL10 Dioxane, 1,4- 1000 Diisopropyl ether VDL11 Methanol500 Water VDL12 Dioxane, 1,4- 1000 Cyclohexane VDL13Methyltetrahydrofuran, 2- 500 Methylcyclohexane VDL14 Methyl-2-butanone,3- 1000 Trimethylpentane, 2,2,4- VDL15 Amylalcohol tert- 1000Trimethylpentane, 2,2,4- VDL16 Dioxane, 1,4- 1000 Water VDL17 Dioxane,1,4- 1000 Octane, n- VDL18 Ethoxyethanol, 2- 500 Water VDL19Methoxyethanol, 2- 500 Water VDL20 Isoamyl acetate 1000 Heptane, n-VDL21 Propionitrile 1000 Chlorobenzene VDL22 Isoamyl acetate 1000Trimethylpentane, 2,2,4- VDL23 Butyronitrile 1000 Chlorobenzene VDL24Butyl acetate 1000 Xylene, p-

Vapor-Diffusion onto Solids

For the vapor diffusion experiments, amorphous ponatinib free base wasexposed to solvent vapors at room temperature for two weeks. The API wasliquid dosed into 8 ml vials and then freeze dried. The 8 ml vials withthe amorphous material were left open and placed in a closed 40 ml vialwith 2 ml of anti solvent (see Table 35 below). After two weeks, thesolids were analyzed by XRPD and digital imaging. If the solids wereliquefied by the vapors, the samples were dried under vacuum (200 mbaror 10 mbar) before they were analyzed by XRPD and digital imaging.

TABLE 35 Experimental Conditions for the Vapor-Diffusion onto SolidsWeight Experiment Anti solvent (mg) VDS1 Chloroform 19.3 VDS2 Methanol18.8 VDS3 Tetrahydrofuran 24.3 VDS4 Diisopropyl ether 22.7 VDS5Trifluoroethanol, 2,2,2- 22.3 VDS6 Hexafluorobenzene 23.7 VDS7Cyclohexane 22.6 VDS8 Acetonitrile 27.1 VDS9 Dichloroethane, 1,2- 24.0VDS10 Thiophene 23.2 VDS11 Dimethylcarbonate 24.4 VDS12 Heptane, n- 25.3VDS13 Trimethylpentane, 2,2,4- 24.5 VDS14 Water 26.1 VDS15 Dioxane, 1,4-24.6 VDS16 Trifluorotoluene, alpha, alpha, alpha- 23.1 VDS17Dimethyl-3-butanone, 2,2- 23.7 VDS18 Octane, n- 25.2 VDS19Dimethylcyclohexane, 1,2- (cis\trans-mixture) 26.1 VDS20 Cyclopentanone24.7 VDS21 Chlorobenzene 26.4 VDS22 Xylene, p- 25.6 VDS23Fluorooctane,1- 28.1 VDS24 Isoamyl acetate 25.2

Physical Stability and Scale-Up of Selected Ponatinib Polymorphs

The purpose of this study was to reproduce and further characterizesolid forms of ponatinib that were identified in the studies discussedherein above. From this study, it was determined that Forms D(isomorphic solvates) and Form F (monohydrate) are physically stable fora period of at least 10 months at ambient conditions. Forms from theB-Class and E-Class, as well as Form G, H, I (low crystalline) and J(low crystalline), converted to Form A over a period of 10 months atambient conditions.

Scale-up of Form H and J (low crystalline) were successful. Scale-upattempt of Form G resulted in Form A. The scale-up project was carriedout in three phases as follows:

Phase 1: investigation of the physical stability by XRPD of the variousforms obtained in the previous studies after storage at ambientconditions for 8-10 months;

Phase 2: scale-up of selected solid forms of ponatinib free base to50-120 mg for further characterization; and

Phase 3: Determination of solvation state, thermal characteristics andphysical stability of the material from phase 2.

Phase 1 Results

Form D (isomorphic solvate) and Form F (monohydrate) are stable for theduration of the study. The isomorphic solvates of Form B-Class and FormE-Class all converted to Form A. Forms G, H, I (low crystalline), and J(low crystalline) all converted to Form A. FIG. 89 presents a tabularsummary of the physical stability of several of the ponatinib solidforms.

Phase 2: Scale Up of Selected Ponatinib Free Base Forms

Forms G, H and J (low crystalline) were selected for scale-up trials.Experimental conditions for the scale-ups were taken from the polymorphscreen disclosed herein. Forms H and J (low crystalline) weresuccessfully scaled-up. FIG. 90 presents a tabular summary of theresults from the scale-up experiments for selected free base forms.

Phase 3: Characterization of the Forms Obtained in the Scale-Up

The solid forms that were scaled up in the previous phase and of whichthe form was confirmed by XRPD were further characterized by: DSC, TGMS,FTIR, HPLC and DVS. Form A resulting from the attempts to scale-up FormG was not further characterized. In addition the physical stability toaccelerated ageing conditions (one week at 40° C. and 75% RH) wasinvestigated. FIG. 91 presents a tabular summary of variouscharacterizations of ponatinib free base forms successfully reproducedat the 120 mg scale.

Pharmaceutical Compositions and Treatment of Physiological ConditionsTherewith

The present disclosure provides pharmaceutical compositions thatcomprise a therapeutically effective amount of a crystalline form ofponatinib hydrochloride disclosed herein and at least onepharmaceutically acceptable carrier, vehicle or excipient. A unit dosageform of a pharmaceutical composition comprises in certain embodiments asingle crystal form of ponatinib hydrochloride as the API.Alternatively, a unit dosage form of a pharmaceutical compositioncomprises more than one crystal form of ponatinib hydrochloride. Incertain embodiments, more than about 50%, more than about 70%, more thanabout 80%, or more than about 90%, of a single crystalline form presentin the composition is of one of the selected forms. In any of theforegoing embodiments, one or all of the crystal forms is substantiallypure. For example, a pharmaceutical composition comprises in certainembodiments substantially pure Form A of ponatinib hydrochloride and atleast one pharmaceutically acceptable carrier, vehicle or excipient.Alternatively, a pharmaceutical composition comprises Form A and Form Jof ponatinib hydrochloride and at least one pharmaceutically acceptablecarrier, vehicle or excipient. Other variations of this theme will bereadily apparent to those of skill in the art given the benefit of thisdisclosure.

The at least one pharmaceutically acceptable carrier, diluent, vehicleor excipient can readily be selected by one of ordinary skill in the artand will be determined by the desired mode of administration.Illustrative examples of suitable modes of administration include oral,nasal, parenteral, topical, transdermal, and rectal. The pharmaceuticalcompositions disclosed herein may take any pharmaceutical formrecognizable to the skilled artisan as being suitable. Suitablepharmaceutical forms include solid, semisolid, liquid, or lyophilizedformulations, such as tablets, powders, capsules, suppositories,suspensions, liposomes, and aerosols.

Various solid forms of ponatinib, and various solid forms of ponatinibhydrochloride, may be administered singly or in any combination at atherapeutically effective amount to a subject in need of treatment.Similarly, any of the solid forms of ponatinib and ponatinibhydrochloride disclosed herein may be formulated singly or in anycombination into a pharmaceutical composition that can be subsequentlyused to treat various disease states in humans or other animals. Forexample, pharmaceutical compositions comprising any single one orcombination of polymorphs of ponatinib and/or ponatinib hydrochloridemay be used for treating CML or Ph+ ALL in a subject in need thereof, bythe administration of a therapeutically effective amount of thepharmaceutical composition to the subject in need thereof.

III. Synthesis of Ponatinib and Ponatinib Hydrochloride

Ponatinib free base and Ponatinib HCl are the products of the convergentfour step synthesis depicted in Scheme 1. Step 1 involves the synthesisof the “methyl ester” intermediate AP25047 from starting materialsAP24595, AP28141, and AP25570. Step 2 involves the synthesis of the“aniline” intermediate, AP24592, from starting material AP29089. Step 3is the base catalyzed coupling of AP25047 and AP24592 to generateponatinib free base, also designated as AP24534, which is isolated asthe free base. Step 4 is the formation and crystallization of themono-hydrochloride salt of ponatinib in ethanol.

A representative route of synthesis of ponatinib HCl is designated asProcess C.

Step 1: Synthesis of AP25047 (“Methyl Ester”) Intermediate

Summary and Synthetic Scheme

Step 1 of the ponatinib HCl process is the synthesis of the methyl esterintermediate AP25047 in a three reaction sequence (designated 1a, 1b,and 1c), carried out without intermediate isolation (“telescoped”), fromstarting materials AP24595, AP25570, and AP28141, as depicted inScheme 1. The array of two aromatic ring systems connected by a singlealkyne linker is constructed through two tandem,palladium/copper-catalyzed Sonogashira couplings and an in situdesilylation reaction under basic conditions. The crude AP25047 productis then subjected to a series of processing steps designed to removeresidual inorganic catalysts and process by-products. These operationsinclude the crystallization of AP25047 as the HCl salt from a non-polarsolvent, toluene (Unit Operation 1.3), an aqueous work-up and silica gelplug filtration (Unit Operation 1.4), and crystallization from a polarsolvent, 2-propanol (Unit Operation 1.5). The two crystallizationsprovide orthogonal purifications for rejection of related substanceimpurities with differing polarities. The crystallization and solventwash of the HCl salt from toluene is controlled by an in-processanalytical test for a specific process impurity. The finalcrystallization of the AP25047 intermediate from 2-propanol has beensubjected to multi-variate DoE studies to define the design space forrobust rejection of other impurities arising from the telescopedreactions. A series of eight in-process tests in Step 1 providequantitative, analytical control for reaction completions, impurityrejection, and effective removal of residual solvents.

Unit Operation 1.1: 1^(st) Sonogashira Reaction

AP24595, palladium tetrakis triphenylphosphine (Pd(PPh₃)₄), copper (I)iodide (CuI), triethylamine, and tetrahydrofuran (THF) are charged tothe reactor. The mixture is stirred and degassed with nitrogen and thenpre-degassed AP28141 is charged. The resulting mixture is brought to45-55° C. and held for not less than 3 hours. The reaction completion isdetermined by IPC-1 (HPLC). If the IPC-1 criterion is met, the mixtureis concentrated to a target volume and cooled.

Unit Operation 1.2: Deprotection/2^(nd) Sonogashira Reaction

AP25570, additional palladium tetrakis triphenylphosphine (Pd(PPh₃)₄),copper (I) iodide (CuI), and tetrahydrofuran (THF) are charged to thereactor. The mixture is concentrated and the water content is determinedby IPC-2 (KF). If the IPC-2 criterion is met, the mixture is warmed to45-60° C. and 25% sodium methoxide solution in methanol is slowly added.The reaction mixture is stirred and held for 30-60 minutes at 45-55° C.The reaction progress is determined by IPC-3 (HPLC). The reactionmixture may be held at a lower temperature during the IPC analysis. Ifthe IPC-3 criterion is met, the process is continued to Unit Operation1.3.

Unit Operation 1.3: Isolation of AP25047•HCl

While stirring, the cool reaction mixture is quenched by addition ofhydrogen chloride gas. A precipitate forms, and residual hydrogenchloride is removed from the suspension by a nitrogen purge.Tetrahydrofuran (THF) is replaced with toluene by an azeotropicdistillation under reduced pressure. The resulting warm slurry isfiltered in an agitated filter dryer and the filter cake is trituratedand washed with warm toluene. The content of process impurity AP29116 isdetermined by IPC-4 (HPLC). If the IPC-4 criterion is met, the wetfilter cake is dried with agitation under a flow of nitrogen and reducedpressure at 35-45° C. (jacket temperature). The drying is monitored byIPC-5 (LOD, gravimetric). If the IPC-5 criterion is met, the crudeAP25047 HCl is discharged and packaged in FEP bags in a plasticcontainer. The isolated AP25047 HCl can be held for up to 7 days priorto forward processing.

Unit Operation 1.4: Work-Up

The crude AP25047 HCl solid is charged to a reactor with dichloromethane(DCM) and washed with aqueous ammonia. The aqueous phase is backextracted with DCM for yield recovery purposes and the combined organicphase is washed a second time with aqueous ammonia. The organic layer isthen washed with aqueous hydrochloric acid until the aqueous phasereaches a pH of 1-2, as indicated by IPC-6 (pH strips). If the IPC-6criterion is met, the organic phase is treated with aqueous sodiumbicarbonate until the aqueous wash reaches a pH of NLT 7, as indicatedby IPC-7 (pH strips). The organic phase is briefly concentrated followedby the addition of fresh dichloromethane. The organic solution is passedthrough a silica gel pad, which is then rinsed with additional freshdichloromethane for increased product recovery.

Unit Operation 1.5: Crystallization of AP25047

The dichloromethane solution is concentrated under reduced pressure, andthe dichloromethane is replaced with 2-propanol by azeotropicdistillation under reduced pressure to the targeted final volume range.The resulting suspension is then cooled and further aged with agitation.

Unit Operation 1.6: Isolation/Drying

The precipitated product is isolated in an agitated filter dryer under aflow of nitrogen, and the filter cake is rinsed with 2-propanol. The wetfilter cake is dried with agitation under a flow of nitrogen and reducedpressure at 45−55° C. (jacket temperature). The drying is monitored byIPC-8 (LOD, gravimetric). If the IPC-8 criterion is met, the product issampled and packaged into polyethylene bags and placed within a heatsealed mylar coated aluminum foil bag, within an HDPE shipping container(Expected yield range, 65-89%).

Step 2: Synthesis of AP24592 (“Aniline”) Intermediate Summary andSynthetic Scheme

Step 2 of the ponatinib HCl process is the synthesis of the anilineintermediate, AP24592, by catalytic hydrogenation of the nitro-aromaticstarting material AP29089, as depicted below. The reaction is carriedout in ethyl acetate, a solvent in which the starting material andproduct are highly soluble. The catalyst for this reaction is palladiumon carbon, and hydrogen is introduced as a gas directly into thereaction mixture. At the completion of the reaction, a solvent exchangefrom ethyl acetate to n-heptane via distillation prompts the spontaneouscrystallization of AP24592, resulting in material with high purity. Thiscrystallization has been shown to have a significant purificationeffect, as most of the process impurities remain solubilized inn-heptane.

The three in-process controls in Step 2 are an HPLC of the reactionmixture to confirm consumption of starting material, a GC measurement ofethyl acetate following the azeotropic solvent exchange to n-heptane,and a gravimetric determination of solvent loss on drying.

Unit Operation 2.1: Dissolution and Hydrogen Purging

AP29089, 10% palladium on carbon, and ethyl acetate are charged to areactor, and the suspension is stirred under hydrogen pressure.

Unit Operation 2.2: Hydrogenation

The reactor is pressurized with hydrogen until a stable pressure rangeis achieved and the mixture is then stirred under hydrogen atmospherefor at least 4 additional hours. The reactor is depressurized and asample taken to assess reaction completion (IPC-1). If the IPC-1criterion is met, the process is continued to Unit Operation 2.3

Unit Operation 2.3: Concentration/Crystallization

The reaction mixture is passed through a filter cartridge to remove thecatalyst, and the cartridge is washed with additional ethyl acetate. Thecombined filtrate and wash solution is concentrated under vacuum toremove a target volume of ethyl acetate. n-Heptane is charged, and thedistillation is continued under vacuum to a target volume. The ethylacetate content is determined by IPC-2 (GC). If the IPC-2 criterion ismet, the process is continued to Unit Operation 2.4.

Unit Operation 2.4: Isolation/Drying

The solid product is dried under vacuum at a target temperature range.The end of drying is determined by IPC-3 (LOD, gravimetric). AP24592 isobtained as a white to yellow solid in a range of 80-97% (based onAP29089 input).

Step 3: Synthesis of Ponatinib Free Base Summary and Synthetic Scheme

Step 3 is the synthesis of the free base of ponatinib by thebase-catalyzed reaction of AP25047 and AP24592, presented in Scheme 4.The reaction is carried out in the presence of a strong base, potassiumtert-butoxide, under essentially water-free conditions to minimize theundesired hydrolysis of the methyl ester of AP25047 to the correspondingunreactive carboxylic acid. The presence of this by-product results innot only loss of yield, but in complications in downstream processingduring the reaction workup. Drying of the reaction mixture by a seriesof azeotropic distillations, controlled by an in-process test for water,ensures a robust reaction and nearly quantitative consumption ofstarting materials. The parameters of the reaction conditions andcrystallization, in which process impurities are robustly rejected, arewell understood on the basis of DoE studies.

Unit Operation 3.1: Drying Reaction Mixture

AP25047, AP24592, and 2-methyl tetrahydrofuran (2-Me-THF) are charged toa reactor. The mixture is concentrated at reduced pressure to a targetvolume. Additional 2-methyl tetrahydrofuran is added and thedistillation repeated. Following another charge of 2-methyltetrahydrofuran and a distillation cycle, the water content of themixture is determined in IPC-1(KF). If the IPC-1 criterion is met, theprocess is continued to Unit Operation 3.2.

Unit Operation 3.2: Reaction

The suspension is maintained with stirring at a target temperature of13-23° C. range while potassium tert-butoxide (KOtBu) is charged. Aftera period of not less than 3 hours, the reaction progress is determinedby HPLC (IPC-2). If the IPC criterion is met, the process is continuedto Unit Operation 3.3.

Unit Operation 3.3: Quench and Extractions

The reaction mixture is diluted with 2-methyltetrahydrofuran (2-Me-THF),and quenched by the addition of aqueous sodium chloride solution. Theorganic layer is separated and the aqueous layer is extracted twice with2-methyl tetrahydrofuran. The combined organic layers are sequentiallywashed with aqueous sodium chloride and water. The organic layer is thenaged at 15-30° C.

Unit Operation 3.4: Concentration/Solvent Exchange

After aging (see Unit Operation 3.3), the mixture is passed through acartridge filter and concentrated under vacuum to a target volume.1-Propanol is charged and allowed to stir at elevated temperature tofurnish a solution, which is distilled under vacuum to a target volumeand then cooled slowly to a temperature range of 20-30° C.

Unit Operation 3.5: Crystallization

The product solution in 1-propanol is aged with stirring at atemperature of 20-30° C. until the presence of solids is visuallyobserved. Acetonitrile is charged to the suspension with stirring andthe resulting suspension is aged for an additional 60-120 minutes at20-30° C. with agitation prior to isolation in the next Unit Operation.

Unit Operation 3.6: Isolation/Drying

The slurry generated in Unit Operation 3.5 is isolated under vacuum in afilter/dryer. The solids are washed twice with a mixture of 1-propanoland acetonitrile. The solids are then dried under vacuum and monitoredby IPC-3 (LOD, gravimetric). If the IPC criterion is met, the product isdischarged as an off-white to yellow solid and packaged in doublepolyethylene bags for storage at ambient temperatures.

Step 4: Synthesis of Ponatinib HCl Summary and Synthetic Scheme

Step 4 of the ponatinib HCl process is the formation of themono-hydrochloride salt through combination of equimolar quantities ofponatinib free base with hydrochloric acid in ethanol and induction ofcrystallization through seeding. The parameters of this process havebeen examined in DoE studies for effects on the generation of thedesired solid form and particle size distribution of this process. Thesynthetic scheme for Step 4 is presented in Scheme 5.

Unit Operation 4.1: Dissolution

AP24534 free base and absolute ethanol (EtOH) are charged to a reactorand stirred at 60-75° C. to generate a solution. Dissolution is verifiedby visual observation.

Unit Operation 4.2: Clarification

The solution is passed through a filter, which is then washed withethanol at 60-78° C.

Unit Operation 4.3: Acidification/Seeding

The product solution is concentrated under vacuum to a target volume.With stirring, an initial portion (approximately 25%) of a solution of1N hydrogen chloride in ethanol is then charged to the reactor. Thesolution is treated with qualified seed crystals of AP24534 HCl at atemperature of 60-70° C. to initiate crystallization. The process iscontinued to Unit Operation 4.4.

Unit Operation 4.4: Crystallization

Once the presence of solids in the reactor is verified by visualobservation, the remainder (approximately 75%) of the 1N hydrogenchloride solution in ethanol is slowly added to the stirred mixture. Themixture is aged for at least 10 minutes and IPC-1 is performed todetermine the pH of the solution. If the IPC criterion is met, themixture is cooled to a temperature of 5-15° C. and aged with stirring.

Unit Operation 4.5: Isolation/Drying

The solid product is isolated by filtration and washed with ethanol at atemperature of 5-15° C. Excess ethanol is removed from the solid productby slow agitation and nitrogen flow at ambient temperature. The solid isthen dried under vacuum at 60-70° C. The drying is monitored by IPC-2(LOD, gravimetric). If the IPC-2 criterion is met, ponatinib HCl isdischarged as an off-white to yellow solid and packaged in doublepolyethylene bags for storage in plastic drums at 20-30° C.

It is to be understood that the foregoing description is exemplary andexplanatory in nature, and is intended to illustrate the presentlydisclosed general inventive concept and its preferred embodiments.Through routine experimentation, those of skill in the art given thebenefit of the instant disclosure may recognize apparent modificationsand variations without departing from the spirit and scope of thepresent disclosure. Thus, the present disclosure is not limited by theabove description, but rather by the following claims and theirequivalents.

1. Crystalline 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride. 2-13. (canceled)
 14. The crystalline 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride of claim 1 which is crystalline Form B of ponatinib hydrochloride. 15-17. (canceled)
 18. The crystalline 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride of claim 1 which is crystalline Form C of ponatinib hydrochloride. 19-21. (canceled)
 22. The crystalline 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride of claim 1 which is crystalline Form D of ponatinib hydrochloride. 23-25. (canceled)
 26. The crystalline 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride of claim 1 which is crystalline Form E of ponatinib hydrochloride.
 27. (canceled)
 28. The crystalline 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride of claim 1 which is crystalline Form F of ponatinib hydrochloride. 29-31. (canceled)
 32. The crystalline 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride of claim 1 which is crystalline Form G of ponatinib hydrochloride.
 33. (canceled)
 34. The crystalline 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride of claim 1 which is crystalline Form H of ponatinib hydrochloride. 35-37. (canceled)
 38. The crystalline 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride of claim 1 which is crystalline Form I of ponatinib hydrochloride.
 39. (canceled)
 40. The crystalline 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride of claim 1 which is crystalline Form J of ponatinib hydrochloride. 41-42. (canceled)
 43. The crystalline 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride of claim 1 which is crystalline Form K of ponatinib hydrochloride. 44-45. (canceled)
 46. A pharmaceutical composition comprising a therapeutically effective amount of crystalline ponatinib hydrochloride and a pharmaceutically acceptable carrier, vehicle or excipient.
 47. (canceled)
 48. The pharmaceutical composition of claim 46, wherein the crystalline ponatinib hydrochloride is Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, or a combination of any of the foregoing.
 49. (canceled)
 50. A method for treating chronic myeloid leukemia or Philadelphia chromosome positive acute lymphoblastic leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of crystalline ponatinib hydrochloride.
 51. (canceled)
 52. The method of claim 50, wherein the crystalline ponatinib hydrochloride is Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, or a combination of any of the foregoing.
 53. (canceled)
 54. Crystalline 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide. 55-125. (canceled) 